Press Release: Santhera Announces Positive Results with Lonodelestat in Early Phase Cystic Fibrosis Trial

Pratteln, Switzerland, March 1, 2021 -- Santhera Pharmaceuticals (SIX:

SANN) announces positive results from its multiple ascending dose Phase

1b study with lonodelestat, a potent inhibitor of human neutrophil

elastase (hNE), in patients with cystic fibrosis (CF).

Lonodelestat is a potent and selective peptide inhibitor of human

neutrophil elastase (hNE), currently being developed in cystic fibrosis

(CF). Neutrophil elastase is an enzyme associated with tissue

inflammation, leading to degradation of the lung tissue in cystic

fibrosis and several other pulmonary diseases. Data from previous Phase

1a studies demonstrated that single dose inhalation of lonodelestat can

lead to high drug concentrations within sputum, resulting in effective

hNE inhibition [1, 2].

The double-blind, placebo-controlled dose-escalation Phase 1b study in

patients with CF assessed the safety, tolerability, pharmacokinetics and

pharmacodynamics of orally inhaled multiple daily doses of lonodelestat

for up to four weeks (clinicaltrials.gov id: NCT03748199). In addition,

the study investigated proof of mechanism of lonodelestat by measuring

activity of hNE, an inflammatory biomarker for monitoring of disease

progression in CF. Santhera acknowledges the support of the Cystic

Fibrosis Foundation (CFF) by providing funding for the conduct of the

Phase 1a and 1b safety trials with lonodelestat.

A total of 32 patients were randomized in four cohorts of eight patients

each and received lonodelestat starting with 80 mg once daily (QD), 80

mg twice daily (BID), 160 mg QD, each administered for 15 days, followed

by a last cohort with 40 mg QD administered for 28 days which was chosen

after observing an effect on forced expiratory volume in 1 second (FEV1)

in some patients treated with the highest doses (80 mg BID and 160 mg

QD). In all four cohorts and over all treatment durations, lonodelestat

demonstrated a good tolerability and no serious side effects (SAEs or

AEs Grade 3 or higher) were reported by the patients. Results showed a

linear dose-exposure relationship over the dose range from 40 mg to 160

mg, with no accumulation in plasma or sputum. In all cohorts, a

transient, near complete inhibition of elastase activity was observed

after inhalation. In addition, in some patients in the 40 mg QD cohort,

a constant level of near complete inhibition gradually developed over

the 28 days of drug inhalation. The results from the safety analyses and

the confirmed effect on the hNE biomarker by lonodelestat are very

encouraging for further development in CF and other inflammatory lung

diseases and have established a safe dose regimen. The findings from

this study will be taken into account in the design of future studies.

"This study provides promising data on the safety of lonodelestat and

its potential to inhibit elastase in cystic fibrosis and maybe other

chronic inflammatory conditions of the lung where neutrophils play a

prominent role in the disease process," said Marcus Mall, MD, Professor

and Head of Department of Pediatric Respiratory Medicine, Immunology and

Critical Care Medicine at the Charité-Universitätsmedizin

Berlin. "The landscape of treatment options for patients with cystic

fibrosis has changed in the recent years with the approval of new drugs,

but there is still a medical need for drugs like lonodelestat that

counteract the chronic inflammation and degradation of lung tissue which

contributes to pulmonary exacerbations. Lonodelestat may add a new

treatment modality for CF patients and I am very excited about the

future development of lonodelestat and the next study."

"We are very much encouraged by the trial results which support the

hypothesis that lonodelestat may possess properties to counteract

underlying inflammatory processes and which indicate treatment was well

tolerated in patients with CF. This demonstrates for the first time that

complete inhibition of neutrophil elastase can be achieved over a

prolonged treatment duration by local delivery through inhalation. We

would like to thank the patients, the investigators and their study

teams for their participation in this study," said Dario Eklund, CEO of

Santhera. "After additional analyses of the results, we will be

optimizing the further clinical development program to advance

lonodelestat for the treatment of CF. In parallel, we are proactively

pursuing collaborations with partners to assess and exploit the

potential of lonodelestat in other pulmonary diseases"

References:

[1] Sellier Kessler O et al. Effect of POL6014, a potent and selective

inhaled neutrophil elastase inhibitor, in a rat model of lung neutrophil

activation. Am J Respir Crit Care Med 2018; 197: A2988

https://www.globenewswire.com/Tracker?data=eJgU6qi4BR3T7tNzSC_PeprHY88k0rSNHFl-FQ5JxHQHnp7JvJ60q8S5gU12kC4y3JBhv05T0S8U7H1D6IsrNJMk9AOBIUEN635WAt3kGsJGqrt_jXch9K8-FcaC8Vv1b9vYcefct5JU0lcFNh6cpFZxUdT21unTb0YwcgXOuzgooOPHSvUE5xsxGVBf6gz_RXSZcQFB7unKL7FisBfzVQNVDYfg22WXPdt3FY2IkMI=

[2] Lagente V et al. A novel protein epitope mimetic (PEM) neutrophil

elastase (NE) inhibitor, POL6014, inhibits human NE-Induced acute lung

injury in mice. Am J Respir Crit Care Med 2009; 179: A5668

https://www.globenewswire.com/Tracker?data=eJgU6qi4BR3T7tNzSC_PeprHY88k0rSNHFl-FQ5JxHQN5ZfJcDfaVp0Wgr_Gl6AhxpiRdSHwCaAyh545FJIOkJ_OkpOcKPCACM80z_fl2xbD4vqhtG-9b_WKd4tXtO76YH3JZDKQge8RYYRGJJgwDRupBfS9P1VwAp_c710mKNlYY-erLDaKZ_LmMeKWBsTq0zpzW2HLOCnODvBEPqLCXnnL2pwKnxdpqPLXJtoXB9Q=

[3] Barth P et al. Single dose escalation studies with inhaled POL6014,

a potent novel selective reversible inhibitor of human neutrophil

elastase, in healthy volunteers and subjects with cystic fibrosis. J

Cyst Fibros 2020

https://www.globenewswire.com/Tracker?data=jD2j-Jg9GBzvpAYpZFg43AKp58ggOu-wjVdSJg5tW-6iE2EI7apd4CLQ3WNwpQqhydGAezFq3SgFtwqpQq8tLK4yPyS0WmCxblRS65_IV7gv_e6D0lCakECmb9ThVY08

; 19: 299-304

About lonodelestat

Lonodelestat (previously known as POL6014), a highly potent and

selective peptide inhibitor of human neutrophil elastase (hNE), is in

development for the treatment of cystic fibrosis. Santhera obtained the

worldwide, exclusive rights from Polyphor AG to develop and

commercialize lonodelestat in CF and other diseases. In preclinical

studies lonodelestat was effective in animal models of neutrophil

activation in lung tissue and of acute lung injury (ALI) [1, 2].

Currently available clinical data demonstrated that single and multiple

doses (Phase 1b) of lonodelestat when administered by inhalation via an

optimized eFlow(R) nebulizer (PARI Pharma GmbH) can lead to high drug

concentrations within the lung, resulting in inhibition of hNE in sputum

of patients, an enzyme associated with lung tissue inflammation [3]. The

Phase 1b study further confirmed the tolerability of lonodelestat after

treatment of up to four weeks in patients with CF. Lonodelestat may also

show therapeutic benefit for a range of neutrophilic pulmonary diseases

with high medical need such as non-CF bronchiectasis (NCFB), alpha-1

antitrypsin deficiency (AATD), chronic obstructive pulmonary disease

(COPD), acute respiratory distress syndrome (ARDS) or primary ciliary

dyskinesia (PCD). Lonodelestat has EU orphan drug designations (ODD) for

the treatment of CF as well as for AATD and PCD in both EU and US.

About cystic fibrosis

Cystic fibrosis (CF) is a rare, hereditary, life-threatening,

progressive disease affecting approximately 70,000 patients in the U.S.

and Europe and is characterized by persistent lung infection and chronic

inflammation thereby limiting the ability to breathe over time.

Activated or necrotic neutrophils liberate human neutrophil elastase

(hNE) in the lung that causes damage to structural, cellular and soluble

components of the pulmonary microenvironment. High levels of hNE play a

central role in the pathophysiology of CF and correlate with disease

severity as measured by functional lung parameters. Inhibition of hNE is

expected to stop or slow the damage to lung tissue and may help to

improve the overall quality of life for individuals with CF.

About Santhera

Santhera Pharmaceuticals (SIX: SANN) is a Swiss specialty pharmaceutical

company focused on the development and commercialization of innovative

medicines for rare neuromuscular and pulmonary diseases with high unmet

medical need. Santhera has an exclusive license for all indications

worldwide to vamorolone, a first-in-class dissociative steroid with

novel mode of action, currently investigated in a pivotal study in

patients with DMD as an alternative to standard corticosteroids. The

clinical stage pipeline also includes lonodelestat (POL6014) to treat

cystic fibrosis (CF) and other neutrophilic pulmonary diseases as well

as an exploratory gene therapy approach targeting congenital muscular

dystrophies. Santhera out-licensed ex-North American rights to its first

approved product, Raxone(R) (idebenone), for the treatment of Leber's

hereditary optic neuropathy (LHON) to Chiesi Group. For further

information, please visit

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www.santhera.com.

Raxone(R) is a trademark of Santhera Pharmaceuticals.

For further information please contact:

https://www.globenewswire.com/Tracker?data=ATRTeL8tdhbvRjQwGM6aArFk91vvYUUnr0CRKbmTT6uXBakVF5tkuwhPYHovwxyn5phxMDq57cvACLcMLM67KI7uyGH-anYBGJQK_u83YAyp-LkP1LNoDA7FtEdiinmB

public-relations@santhera.com or

Eva Kalias, Head External Communications

Phone: +41 79 875 27 80

eva.kalias@santhera.com

Disclaimer / Forward-looking statements

This communication does not constitute an offer or invitation to

subscribe for or purchase any securities of Santhera Pharmaceuticals

Holding AG. This publication may contain certain forward-looking

statements concerning the Company and its business. Such statements

involve certain risks, uncertainties and other factors which could cause

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