New Ad-hoc Analysis of Phase 3 HELP Study™ Evaluates Prevention of HAE Attacks with TAKHZYRO® (lanadelumab) During Early Treatment Phase

Data Presented at European Academy of Allergy and Clinical
Immunology Congress

OSAKA, Japan–(BUSINESS WIRE)–Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK)
(“Takeda”) today announced new data from an ad-hoc analysis of the Phase
3 HELP Study™, designed to evaluate the onset of action for TAKHZYRO^®
(lanadelumab) during days 0-69 of treatment. The analysis suggests that
TAKHZYRO starts to prevent hereditary angioedema (HAE) attacks during
this early treatment phase, with patients experiencing an 80.1% decrease
in mean monthly attack rate compared to placebo.¹ The results
were presented today (PD0369) during the European Academy of Allergy and
Clinical Immunology (EAACI) Congress in Lisbon, Portugal. HAE is a rare,
genetic and potentially life-threatening disorder that can result in
recurrent attacks of oedema (swelling) in various parts of the body.^2,3

“The unpredictable nature of HAE attacks makes living with the disease
physically and emotionally challenging for patients,” said Professor
Marcus Maurer, M.D., Department of Dermatology and Allergy,
Allergie-Centrum-Charité, Charité–Universitätsmedizin Berlin, Germany.
“HAE requires an individualised approach to treatment, and it is
important that a patient’s treatment plan helps reduce the frequency of
attacks. These results are exciting as they suggest that lanadelumab
begins to prevent HAE attacks during the initial phase of treatment.”

The ad-hoc analysis evaluated the efficacy of TAKHZYRO compared with
placebo during days 0-69 of treatment using the same approach that was
used to evaluate the primary and secondary endpoints during the complete
study period (days 0-182).¹ Results from the analysis showed
that in patients receiving the recommended starting dose of TAKHZYRO 300
mg every two weeks, there was a significant reduction in mean monthly
attack rate (80.1% decrease) compared to placebo (Adjusted P<0.001).¹
During this initial treatment phase, patients treated with TAKHZYRO 300
mg every two weeks also experienced fewer severe attacks compared to
placebo (7.4% vs. 22%) and were more likely to be HAE attack-free
compared to those on placebo (48.1% vs. 7.3%).¹

“Original data from the HELP Study showed that TAKHZYRO was effective in
preventing HAE attacks over the entire duration of the study and,
according to an exploratory analysis, many patients remained attack-free
during the 16-week steady state period,” said Donatello Crocetta, M.D.,
Franchise Global Medical Unit Head, Rare Immunology and HAE at Takeda.
“This new analysis supports previous study findings and builds on our
understanding of how quickly TAKHZYRO can begin to help prevent HAE
attacks, further supporting its use for appropriate patients as a
preventive therapy that can be administered subcutaneously and begins to
work rapidly.”

Across all TAKHZYRO treatment arms, (300 mg every two weeks, 300 mg
every four weeks, 150 mg every four weeks), there was an improvement in
mean monthly attack rate, monthly rate of moderate to severe attacks,
monthly rate of attacks requiring acute treatment and the number of
attack-free days, versus placebo, during the entire study period.¹

The most commonly observed adverse reactions (52.4%) associated with
TAKHZYRO were injection site reactions. Of these, 97% were of mild
intensity. Hypersensitivity reaction (mild and moderate pruritus,
discomfort and tingling of tongue) was observed (1.2%).⁴

TAKHZYRO 300 mg is approved in the European Union and Australia for the
routine prevention of recurrent attacks of HAE in patients aged 12 years
and older. TAKHZYRO 300 mg is approved as prophylaxis to prevent attacks
of HAE in patients aged 12 years and older in the United States and for
the routine prevention of attacks in patients aged 12 years and older in
Canada.

The HELP Study™
The HELP (Hereditary Angioedema Long-term
Prophylaxis) Study™ was a multicentre, randomised, double-blind,
placebo-controlled parallel group trial that evaluated the efficacy and
safety of subcutaneously administered TAKHZYRO vs. placebo over 26 weeks
in 125 patients 12 years of age or older with HAE.⁴

The primary endpoint of the HELP Study™ was the number of
investigator-confirmed HAE attacks over the entire 26-week study
duration. TAKHZYRO demonstrated that subcutaneous injections every two
or four weeks reduced the mean monthly number of attacks across all
three TAKHZYRO treatment arms studies: 300 mg every two weeks, 300 mg
every four weeks and 150 mg of TAKHZYRO every four weeks. At 300 mg
every two weeks, TAKHZYRO reduced the number of mean monthly HAE attacks
by 87% vs. placebo (Adjusted P<0.001).⁴

Secondary endpoints included: 1) number of attacks requiring acute
treatment and 2) number of attacks assessed as moderate or severe.
Overall, each TAKHZYRO treatment arm demonstrated statistically
significant attack rate reductions compared with placebo for all
secondary efficacy endpoints (Adjusted P<0.001 for all comparisons),
including: attacks requiring acute treatment (74% to 87%) and moderate
or severe attacks (70% to 83%).⁴

Complete results from the Phase 3 HELP Study™ were published in the Journal
of the American Medical Association (JAMA) on 27 November 2018.⁵

About Hereditary Angioedema
HAE is a rare genetic disorder
that results in recurring attacks of oedema – swelling – in various
parts of the body, including the abdomen, face, feet, genitals, hands
and throat. The swelling can be debilitating and painful.^2,3,6
Attacks that obstruct the airways can cause asphyxiation and are
potentially life-threatening.^3,6 HAE affects an estimated 1
in 10,000 to 1 in 50,000 people worldwide. It is often under-recognised,
under-diagnosed and under-treated.^2,7

About TAKHZYRO^® (lanadelumab)
TAKHZYRO
(lanadelumab) is a fully human monoclonal antibody that specifically
binds and decreases plasma kallikrein activity. TAKHZYRO is produced in
Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.⁴

TAKHZYRO is formulated for subcutaneous administration and has a
half-life of approximately two weeks in patients with HAE. TAKHZYRO is
intended for the self-administration or administration by a caregiver,
only after training by a healthcare professional.⁴

TAKHZYRO Safety Information for Europe
Please consult the
TAKHZYRO Summary Product Characteristics (SmPC) before prescribing.

TAKHZYRO treatment should be initiated under the supervision of a
physician experienced in the management of patients with hereditary
angioedema (HAE). TAKHZYRO may be self-administered or administered by a
caregiver only after training on SC injection technique by a healthcare
professional.

Contraindication
Hypersensitivity to the active substance or
to any of the excipients.

Warnings and Precautions
Traceability: In order to improve
the traceability of biological medicinal products, the name and the
batch number of the administered product should be clearly recorded.

Hypersensitivity reactions have been observed. In case of a severe
hypersensitivity reaction, administration of TAKHZYRO must be stopped
immediately and appropriate treatment must be initiated.

General: TAKHZYRO is not intended for treatment of acute HAE attacks. In
case of a breakthrough HAE attack, individualized treatment should be
initiated with an approved rescue medication. There are no available
clinical data on the use of lanadelumab in HAE patients with normal
C1-INH activity.

Interference with coagulation test: Lanadelumab can increase activated
partial thromboplastin time (aPTT) due to an interaction of lanadelumab
with the aPTT assay. The reagents used in the aPTT laboratory test
initiate intrinsic coagulation through the activation of plasma
kallikrein in the contact system. Inhibition of plasma kallikrein by
lanadelumab can increase aPTT in this assay. None of the increases in
aPTT in patients treated with TAKHZYRO were associated with abnormal
bleeding adverse events. There were no differences in international
normalised ratio (INR) between treatment groups.

Sodium content: This medicinal product contains less than 1 mmol sodium
(23 mg) per vial, that is to say essentially ‘sodium-free’.

Interactions
No dedicated drug-drug interaction studies have
been conducted. Based on the characteristics of lanadelumab, no
pharmacokinetic interactions with co-administered medicinal products is
expected.

As expected, concomitant use of the rescue medication C1 esterase
inhibitor results in an additive effect on lanadelumab-cHMWK response
based on the mechanism of action (MOA) of lanadelumab and C1 esterase
inhibitor.

Immunogenicity
Treatment with lanadelumab has been
associated with development of treatment emergent anti-drug antibodies
(ADA) in 11.9% (10/84) of subjects. All antibody titres were low. The
ADA response was transient in 20% (2/10) of ADA positive subjects. 2.4%
(2/84) of lanadelumab-treated subjects tested positive for neutralizing
antibodies.

The development of ADA including neutralising antibodies against
TAKHZYRO did not appear to adversely affect the pharmacokinetic (PK) and
pharmacodynamics (PD) profiles or clinical response.

Adverse Reactions
The most commonly observed adverse
reaction (52.4%) associated with TAKHZYRO was injection site reactions
(ISR) including injection site pain, injection site erythema and
injection site bruising. Of these ISRs, 97% were of mild intensity, 90%
resolved within 1 day after onset with a median duration of 6 minutes.

Hypersensitivity reaction (mild and moderate pruritus, discomfort and
tingling of tongue) was observed (1.2%)

Very common (frequency ≥1/10):			Injection site reactions*
Common (≥1/100 to <1/10):			Hypersensitivity**, dizziness, rash maclo-papular, myalgia, alanine aminotransferase increased, aspartate aminotransferase increased.

*Injection site reactions include: pain, erythema, bruising, discomfort,
haematoma, haemorrhage, pruritus, swelling, induration, paraesthesia,
reaction, warmth, oedema and rash.
** Hypersensitivity includes:
pruritus, discomfort and tingling of tongue.

For full U.S. Prescribing Information, including the approved
indication and important safety information, please visit https://www.shirecontent.com/PI/PDFs/TAKHZYRO_USA_ENG.pdf.

About Takeda Pharmaceutical Company Limited
Takeda
Pharmaceutical Company Limited (TSE:4502/NYSE:TAK)
is a global, values-based, R&D-driven biopharmaceutical leader
headquartered in Japan, committed to bringing Better Health and a
Brighter Future to patients by translating science into highly
innovative medicines. Takeda focuses its R&D efforts on four therapeutic
areas: Oncology, Gastroenterology (GI), Neuroscience, and Rare Diseases.
We also make targeted R&D investments in Plasma-Derived Therapies and
Vaccines. We are focusing on developing highly innovative medicines that
contribute to making a difference in people’s lives by advancing the
frontier of new treatment options and leveraging our enhanced
collaborative R&D engine and capabilities to create a robust,
modality-diverse pipeline. Our employees are committed to improving
quality of life for patients and to working with our partners in health
care in approximately 80 countries and regions.
For more
information, visit https://www.takeda.com

¹ Riedl, MA et al. Lanadeluman demonstrates rapid and
sustained prevention of hereditary angioedema attacks: Findings from the
HELP study. Poster Presentation. European Academy of Allergy and
Clinical Immunology. Lisbon, Portugal. June 2019.
²
Cicardi M, Bork K, Caballero T, et al, on behalf of HAWK (Hereditary
Angioedema International Working Group). Evidence-based recommendations
for the therapeutic management of angioedema owing to hereditary C1
inhibitor deficiency: consensus report of an International Working
Group. Allergy. 2012; 67(2):147-157.
³ Zuraw BL.
Hereditary angioedema. N Engl J Med. 2008;359(10):1027-1036.
⁴
TAKHZYRO^® (lanadelumab) Summary of Product Characteristics.
⁵
Banerji A, Riedl MA, Bernstein JA, et al; for the HELP Investigators.
Effect of lanadelumab compared with placebo on prevention of hereditary
angioedema attacks: a randomized clinical trial. JAMA.
2018;320(20):2108-2121.
⁶ Banerji A. The burden of
illness in patients with hereditary angioedema. Ann Allergy Asthma
Immunol. 2013;111(5):329-336.
⁷ Longhurst HJ, Bork K.
Hereditary angioedema: causes, manifestations, and treatment. Br J Hosp
Med. 2006;67(12):654-657.

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