Press Release: Novartis data show potential of remibrutinib as an oral treatment for chronic spontaneous urticaria providing significant symptom improvement ...

-- In pivotal Phase III trials, remibrutinib -- a highly selective, oral

Bruton's tyrosine kinase inhibitor -- demonstrated clinically meaningful

and statistically significant reduction in urticaria activity vs placebo1

-- Treatment with remibrutinib led to significant improvement in symptom

control, as early as Week 2 and sustained up to Week 121

-- Remibrutinib was well-tolerated and demonstrated a favorable safety

profile with rates of overall adverse events comparable to placebo and

balanced liver function tests across both studies1

-- REMIX-1 and REMIX-2 studies are ongoing, with final (52-week) readout and

regulatory submissions in 2024

Basel, November 9, 2023 -- Novartis today announced new positive data from the Phase III REMIX-1 and REMIX-2 studies investigating remibrutinib -- a highly selective, oral Bruton's tyrosine kinase (BTK) inhibitor -- in people with chronic spontaneous urticaria (CSU) whose symptoms are inadequately controlled by H1-antihistamines(1). In the studies, remibrutinib met all primary and secondary endpoints at Week 12(1). Remibrutinib demonstrated superiority in change from baseline vs placebo in weekly urticaria activity (UAS7), itch (ISS7) and hives (HSS7) at Week 12(1). Significantly more patients achieved well-controlled disease (UAS7<=6) with remibrutinib vs placebo, as early as Week 2 which was sustained at Week 12, and about one third of patients achieved complete absence of itch and hives at Week 12(1). Data are being presented at the 2023 American College of Allergy, Asthma and Immunology Scientific Meeting in Anaheim, California, November 9--13.

"These findings could be significant for the millions of people who suffer from CSU and are still symptomatic," said Marcus Maurer, M.D., Professor of Dermatology and Allergy, Executive Director of the Institute of Allergology at Charité -- Universitätsmedizin Berlin and Co-Director of Allergy and Immunology at the Fraunhofer Institute for Translational Medicine and Pharmacology. "Living with CSU can be very distressing, often impacting many aspects of people's lives such as sleep and ability to work. Having another option that could potentially provide effective relief as early as 2 weeks after trying antihistamines alone could be transformative for these patients."

Mean change from baseline (CFB) in UAS7, ISS7 and HSS7 at Week 12 in REMIX-1 and REMIX-2(1)

REMIX-1 REMIX-2

------------- ---------------------------- ----------------------------

LS mean +/-SE Remibrutinib Placebo Remibrutinib Placebo

(n=309) (n=153) (n=297) (n=153)

CFB-UAS7 --20.1 +/-0.7 --13.8 +/-1.0 --19.6 +/-0.7 --11.7 +/-0.9

CFB-ISS7 --9.6 +/-0.3 --6.9 +/-0.5 --9.0 +/-0.3 --5.7 +/-0.5

CFB-HSS7 --10.5 +/-0.4 --6.9 +/-0.5 --10.5 +/-0.4 --6.0 +/-0.5

LS, least squares; SE, standard error.

In pooled safety analyses of the REMIX studies, remibrutinib demonstrated a well-tolerated and favorable safety profile, with overall adverse event rates that were comparable to placebo (64.0% in remibrutinib vs 64.7% in placebo), including infections (32.8% in remibrutinib vs 34.0% in placebo) and liver function test abnormalities. Liver transaminase elevations were balanced across both treatment groups (remibrutinib and placebo), asymptomatic, transient and reversible(1). None of the serious adverse events were considered related to study medication by investigators.

"Patients with CSU have limited treatment options and many patients do not respond to antihistamines even at higher than approved doses, leaving them with uncontrolled symptoms and potential side effects such as drowsiness," said Angelika Jahreis, Global Head, Development, Immunology, Novartis. "We are committed to developing new therapies for patients with immuno-dermatologic disorders and are excited about the prospect to provide a potential new option for patients with CSU who suffer from relentless itch and a life filled with limitations. These data show that remibrutinib, an oral BTKi, provided significant symptom improvement as early as Week 2 and sustained up to Week 12."

Antihistamines are recommended to treat CSU but are not always effective(2). International guidelines recommend increasing the approved dose up to four-fold, but people can still have uncontrolled symptoms, even at high doses(3). While injectable biologic therapies are an effective option for those whose CSU is uncontrolled by antihistamines, less than 20% of eligible patients worldwide are treated with them(4).

CSU is the medical term for chronic hives that last for 6 weeks or longer, where the underlying cause is internal rather than exposure to any allergen or external trigger(5,6). In CSU, BTK is believed to play a role in the signaling pathway that leads to the release of histamine and debilitating symptoms(7). Remibrutinib blocks BTK and prevents the release of histamine that causes itchy hives (wheals) and/or deep tissue swelling (angioedema)(6,8).

Patients currently enrolled in REMIX-1 and REMIX-2 will continue to receive treatment up to Week 52 and will have the opportunity to continue in a long-term extension trial. Novartis intends to submit remibrutinib to global health authorities starting in 2024.

About remibrutinib

Remibrutinib is an investigational highly selective, covalent, oral BTK inhibitor that blocks the BTK cascade and prevents the release of histamine that causes itchy hives (wheals) and swelling(6-8). In Phase III studies, treatment with remibrutinib led to significant improvement in symptom control, as early as Week 2 and sustained up to Week 12(1). Significantly more patients achieved well-controlled disease (UAS7<=6) with remibrutinib vs placebo, as early as Week 2 which was sustained at Week 12, and about one third of patients achieved complete absence of itch and hives at Week 12(1). Remibrutinib has been shown to be well-tolerated with a favorable safety profile, with balanced liver function test results across studies(1). Most commonly observed (occurring in >=3% of patients during the 24-Week double-blind period) adverse events in the Phase III REMIX studies were respiratory tract infections (COVID-19 and nasopharyngitis, both comparable to placebo)(1). In addition to CSU, remibrutinib is being investigated in other immune-mediated conditions, such as multiple sclerosis, hidradenitis suppurativa, food allergy and Sjögren's disease(9-13). If approved, remibrutinib has the potential to become an effective oral option to complement Xolair(R) (omalizumab), the first and only injectable biologic indicated for CSU(14). In the US, Novartis Pharmaceuticals Corporation and Genentech, a member of the Roche Group, work together to develop and co-promote Xolair.

About REMIX-1 and REMIX-2

REMIX-1 (NCT05030311) and REMIX-2 (NCT05032157) are two identically designed global, multicenter, randomized, double-blind, parallel-group, placebo-controlled Phase III studies, with REMIX-1 consisting of 470 participants and REMIX-2 consisting of 455 participants(15,16). Both studies are designed to establish the efficacy, safety, and tolerability of twice-daily remibrutinib 25 mg treatment in adult participants with CSU that is inadequately controlled by second generation H1-antihistamines compared with placebo(15,16). The primary outcome measures include absolute change from baseline in UAS7, absolute change in ISS7 and HSS7 at Week 12(15,16). All participants were on a stable, locally label-approved dose of a second-generation H1-antihistamine throughout the entire study. Patients currently enrolled in REMIX-1 and REMIX-2 will continue to receive treatment up to Week 52 and will have the opportunity to continue in a long-term extension trial(15,16).

About CSU

CSU affects approximately 40 million people worldwide(5,17). It is characterized by the sudden appearance of itchy hives (wheals) and/or deep tissue swelling (angioedema, which can occur on the face, throat, hands, and feet) for more than 6 weeks(6,18). CSU affects all ages but most frequently between the ages of 20--40, with women affected nearly twice as often as men(5). CSU causes significant emotional distress, with the majority of patients suffering from sleep deprivation, and high rates of mental disorders, such as anxiety or depression, as well as impact on their work productivity(5). There are currently limited effective treatment options for CSU, with many patients not achieving full control from the first-line treatment, antihistamines(2).

Disclaimer

This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "may," "could," "would," "expect," "anticipate," "seek," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations

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