New Data from the Phase 3 HELP Study Open-Label Extension Evaluate the Long-Term Safety and Efficacy of TAKHZYRO® (lanadelumab) in Reducing Hereditary Angioedema Attacks

- New Analyses Presented at the European Academy of Allergy and Clinical Immunology Digital Congress

Osaka, JAPAN, June 6, 2020 – Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced findings from two new interim analyses of data from the Phase 3 HELP (Hereditary Angioedema Long-term Prophylaxis) Study™ Open-label Extension (OLE). The analyses suggest that TAKHZYRO^® (lanadelumab) is well-tolerated and can prevent hereditary angioedema (HAE) attacks over an extended treatment period, with sustained and consistent reduction in monthly attack rate across a range of different patient subgroups. The data are being presented at the 2020 European Academy of Allergy and Clinical Immunology (EAACI) Digital Congress.

The original Phase 3 HELP Study was conducted in 125 patients aged 12 years and older over 26 weeks, making it the largest randomised, controlled prevention study in HAE, with the longest active treatment duration, to date.^[1] The HELP Study OLE was designed to evaluate the long-term safety (primary endpoint) and efficacy of TAKHZYRO for up to 2.5 years and was completed in November 2019. These interim analyses were based on data collected between May 2016 and August 2018 and included 109 rollover patients, who were originally evaluated in the HELP Study, and 103 eligible non-rollover patients who did not participate in the initial study but had experienced at least one HAE attack in 12 weeks. At the time of the interim analyses, patients received treatment for a mean duration of 19.7 months (0-26.1).^[2],[3],[4]

“HAE attacks are unpredictable, often painful and can be debilitating for those living with the disease. These data are exciting as they help us better understand the potential of TAKHZYRO to provide sustained prevention and reduce attack frequency long-term, across a range of patient demographics,” said Donatello Crocetta, M.D., Global Medical Head, Rare Immunology and Metabolic Diseases, Chief Medical Office, Takeda. “The HELP Study OLE analyses add to the evidence that supports TAKHZYRO as a leading option in preventive HAE treatments.”

Results from the HELP Study OLE showed that the safety profile of TAKHZYRO was consistent with the original findings from the HELP Study, with treatment-related treatment emergent adverse events (TEAEs) occurring in 50% of patients (n=106).^[5] In addition, data from the HELP Study OLE showed that the efficacy of TAKHZYRO 300 mg administered subcutaneously every two weeks in rollover patients was consistent with the original findings from the HELP Study. A sustained reduction in attack rate was observed in this group, with numerically lower mean monthly attack rates of 0.18 (n=25) during the extended treatment period of the HELP Study OLE and 0.26 (n=25) at the end of the HELP Study.^[6] The efficacy profile of non-rollover patients was similar to efficacy in rollover patients with two years of cumulative study experience in the HELP Study and HELP Study OLE. The median attack rate reduction was consistent across all subgroups, including patient sex, race, HAE type, age, BMI, history of prophylaxis use, history of laryngeal attacks, and baseline attack rate.^[7]

In the study TEAEs occurred in ~95% of patients (N=212) and were mostly mild or moderate in severity. The TEAEs related to treatment that were reported in more than 5% of patients are injection site pain (33.9% of rollover patients [n=37] and 42.7% of non-rollover patients [n=44]), injection site erythema (11.9% of rollover patients [n=13] and 15.5% of non-rollover patients [n=16]) and injection site bruising (4.6% of rollover patients [n=5] and 9.7% of non-rollover patients [n=10]).⁵

Lanadelumab is well-tolerated and effective across patient subgroups: findings from the HELP open-label extension study; OAS 21 Recorded scientific content #1287
In this interim analysis, treatment with TAKHZYRO 300 mg every two weeks was well-tolerated and effectively reduced attack rates over an extended treatment period across different patient demographic and disease characteristics.⁷

According to the interim analysis, the median attack rate reduction was consistent regardless of patient sex (98.6% reduction in males (n=69), 97.4% females (n=143); race (97.8% white (n=198), 95.9% non-white (n=14)); HAE type (97.6% type 1 (n=189), 97.4% type 2 (n=21)); age (97.4% <18 years (n=21), 97.4% 18-40 years (n=77), 98.4% 40-65 years (n=103), 92.0% ≥65 years (n=11)); BMI (98.5% normal (n=61), 97.5% overweight (n=60), 97.1% obese (n=59)); history of long-term prophylaxis use (97.2% C1-INH use (n=106), 97.1% no LTP (n=87)); history of laryngeal attacks (97.1% yes (n=130), 99.8% no (n=82)); and baseline attack rate (92.2% <1 attack/month (n=25), 100% 1-<2 attacks/month (n=74), 98.1% 2-<3 attacks/month (n=30), 96.5% ≥3 attacks/month (n=83)).⁷

The safety profile of TAKHZYRO was comparable across all subgroups, with treatment-related treatment emergent adverse events (TEAEs) occurring in 50% of patients (n=106) and the most common being mild injection site pain.⁷

Efficacy of lanadelumab is durable over time: Findings from the HELP Study and HELP OLE; OAS 21 Recorded scientific content #1096
According to the interim analysis, treatment with TAKHZYRO 300 mg every two weeks demonstrated sustained reductions in HAE attack rates in patients who received treatment for a mean duration of 19.7 months (0-26.1).⁶

At the end of the HELP Study and at the start of the HELP Study OLE, the mean attack rates per month in the patients receiving TAKHZYRO 300 mg every two weeks ranged from 0.26 (n=25) for the treatment group and 2.39 (n=33) for the control group. For patients treated with TAKHZYRO 300 mg every two weeks in the original HELP Study, sustained reductions in HAE attacks were observed in the HELP Study OLE, with a mean monthly attack rate of 0.18 (n=25).⁶

Similarly, further numerical reductions were also shown for the number of attacks requiring acute treatment and for the rate of moderate or severe attacks for this group as well as for patients receiving TAKHZYRO 300 mg every four weeks in the HELP Study (n=25).⁶

The efficacy profile of non-rollover patients was similar to efficacy in rollover patients with two years of cumulative study experience in the HELP Study and HELP Study OLE.⁶

Takeda will present the following analyses during the EAACI Digital Congress:

• An open-label, multicentre phase 3 study evaluating lanadelumab for the prevention of hereditary angioedema attacks in paediatric patients: SPRING study design; TPS 07 Recorded scientific content (#1490)
• Evaluation of long-term effectiveness of lanadelumab for hereditary angioedema in real-world clinical practice: design of the ENABLE study; PDS 06 Recorded scientific content (#1126)
• Effectiveness of Lanadelumab in the Real-World Setting: Findings from a Temporary Authorization of Use (ATU) in France for the Treatment of Hereditary Angioedema Type 1/2; PDS 06 Recorded scientific content (#1285)
• The Relationship between Treatment with Long-Term Prophylaxis and Attack Rate in Hereditary Angioedema (HAE): A Multinational Chart Review Study; PDS 06 Recorded scientific content (#1216)
• Treatment-Specific Normalization of Plasma Kallikrein Activity Observed in Patients with Hereditary Angioedema (HAE); PDS 06 Recorded scientific content (#708)
• A Novel Dried Blood Spot Assay of Functional C1 Inhibitor Activity from Patients with Hereditary Angioedema; DCPD 07 Recorded scientific content (#675)
• Implementation of a novel DBS-based methodology to diagnose hereditary angioedema in subjects with recurrent abdominal pain of unclear etiology – the international EHA study; OAS 21 Recorded scientific content (#1475)
• Study to evaluate metabolomic profiling of hereditary angioedema and identify candidate biomarkers for disease monitoring (HAEKA Study); PDS 06 Recorded scientific content (#1360)
• Effectiveness of icatibant to control symptoms of HAE attacks in real-world clinical practice; PDS 06 Recorded scientific content (#1300)
• Treatment of acute attacks of hereditary angioedema due to C1 inhibitor deficiency with icatibant in paediatric versus adult patients: findings from the Icatibant Outcome Survey; PDS 06 Recorded scientific content (#1333)
• Long-term effectiveness and safety of icatibant for the on-demand treatment of hereditary angioedema attacks: 10 years of the Icatibant Outcome Survey; OAS 21 Recorded scientific content (#1118)

All of the presentations are available throughout the duration of the digital congress via the online scientific programme.

About The HELP Study^™ Open-label Extension
The HELP (Hereditary Angioedema Long-term Prophylaxis) Study^™ Open-label Extension (OLE) is an evaluation of the long-term efficacy and safety of TAKHZYRO in hereditary angioedema (HAE) patients of at least 12 years of age and older. Two hundred and twelve patients received treatment with TAKHZYRO at the start of the OLE Study (109 rollover patients originally evaluated in the HELP Study and who continued into the OLE, and 103 eligible patients who did not participate in the HELP study but who had experienced at least one attack in 12 weeks). Rollover patients received a dose of 300 mg TAKHZYRO on Day 0 and then every two weeks after their first attack. Non-rollover patients were treated with one 300 mg dose every two weeks, beginning on Day 0. One hundred and ninety-three participants completed at least 12 months of treatment and 27 participants completed at least 24 months of treatment at the time of the interim analyses.^2,3,4

About Hereditary Angioedema
Hereditary angioedema (HAE) is a rare genetic disorder that results in recurrent 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.^[8],[9],[10] Attacks that obstruct the airways can cause asphyxiation and are potentially life threatening.^8,9 HAE affects an estimated 1 in 50,000 people worldwide. It is often under-recognized, under-diagnosed and under-treated.^8,[11]

About TAKHZYRO^® (lanadelumab)
TAKHZYRO (lanadelumab) is indicated for routine prevention of recurrent attacks HAE in patients aged 12 years and older. TAKHZYRO 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.^[12]

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.¹²

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.¹²

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 European Union Summary of Product Characteristics, please visit
https://www.ema.europa.eu/en/documents/product-information/takhzyro-epar-product-information_en.pdf.

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, Rare Diseases, Neuroscience, and Gastroenterology (GI). 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.
For more information, visit https://www.takeda.com.


Media Contacts:

Japanese Media
Kazumi Kobayashi
[email protected]
+81 (0) 3-3278-2095

Media outside Japan
Emily Bunting
[email protected]
+41 79 866 9703


Important Notice
For the purposes of this notice, “press release” means this document, any oral presentation, any question and answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) regarding this release. This press release (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this press release. No offering of securities shall be made in the United States except pursuant to registration under the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This press release is being given (together with any further information which may be provided to the recipient) on the condition that it is for use by the recipient for information purposes only (and not for the evaluation of any investment, acquisition, disposal or any other transaction). Any failure to comply with these restrictions may constitute a violation of applicable securities laws.
The companies in which Takeda directly and indirectly owns investments are separate entities. In this press release, “Takeda” is sometimes used for convenience where references are made to Takeda and its subsidiaries in general. Likewise, the words “we”, “us” and “our” are also used to refer to subsidiaries in general or to those who work for them. These expressions are also used where no useful purpose is served by identifying the particular company or companies.

Forward-Looking Statements
This press release and any materials distributed in connection with this press release may contain forward-looking statements, beliefs or opinions regarding Takeda’s future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements often include words such as “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “aims”, “intends”, “ensures”, “will”, “may”, “should”, “would”, “could” “anticipates”, “estimates”, “projects” or similar expressions or the negative thereof. These forward-looking statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those expressed or implied by the forward-looking statements: the economic circumstances surrounding Takeda’s global business, including general economic conditions in Japan and the United States; competitive pressures and developments; changes to applicable laws and regulations; the success of or failure of product development programs; decisions of regulatory authorities and the timing thereof; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the impact of health crises, like the novel coronavirus pandemic, on Takeda and its customers and suppliers, including foreign governments in countries in which Takeda operates, or on other facets of its business; the timing and impact of post-merger integration efforts with acquired companies; the ability to divest assets that are not core to Takeda’s operations and the timing of any such divestment(s); and other factors identified in Takeda’s most recent Annual Report on Form 20-F and Takeda’s other reports filed with the U.S. Securities and Exchange Commission, available on Takeda’s website at: https://www.takeda.com/investors/reports/sec-filings/ or at www.sec.gov. Takeda does not undertake to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results or statements of Takeda in this press release may not be indicative of, and are not an estimate, forecast, guarantee or projection of Takeda’s future results.

---

^[1] 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.

^[2] K. Paes, Craig T, Bernstein JA, Longhurst HJ, et al; for the HELP OLE Study Investigators. Efficacy of Lanadelumab in Hereditary Angioedema Patients With and Without Prior Long-Term Prophylaxis Use: Interim Results From the HELPOpen-Label Extension Study. AAAAI 2020.

^[3] Banerji A, Riedl MA, Tachdjian R, et al; for the HELP OLE Study Investigators. Consistent Reduction in HAE Attack Rate with Lanadelumab Regardless Of Baseline Attack Frequency: Interim Findings From the Phase 3 HELP Study Open Label Extension (OLE). AAAAI 2020. Abstract #319.

^[4] Riedl MA, Johnston DT, Lumry WR, et al. Attack-Free Status of Patients With Hereditary Angioedema (HAE) During Extended Treatment With Lanadelumab in the HELP OLE Study. AAAAI 2020.

^[5] Johnston DT, Banerji A, Nurse C, et al; for the HELP OLE Study Investigators. Long-Term Safety of Lanadelumab in Hereditary Angioedema (HAE): Interim Results From the HELP OLE Study.
ACAAI 2019.

^[6] Kiani S et al. Efficacy of lanadelumab is durable over time: Findings from the HELP Study and HELP OLE. EAACI 2020. OAS 21 Recorded scientific content #1096

^[7] Maurer M et al. Lanadelumab is well-tolerated and effective across patient subgroups: findings from the HELP open-label extension study. EAACI 2020. OAS 21 Recorded scientific content #1287

^[8] 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.

^[9] Zuraw BL. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-1036.

^[10] Banerji A. The burden of illness in patients with hereditary angioedema. Ann Allergy Asthma Immunol.
2013;111(5):329-336.

^[11] Longhurst HJ, Bork K. Hereditary angioedema: causes, manifestations, and treatment. Br J Hosp Med.
2006;67(12):654-657.

^[12] TAKHZYRO^® (lanadelumab) European Summary of Product Characteristics.