March 23, 2018
Press Release
Nobelpharma Co., Ltd.
SAKIGAKE Designation & Orphan Drug Designation
RAPALIMUS GEL 0.2% (mTOR inhibitor), Treatment for Angiofibroma in Tuberous Sclerosis
Marketing Approval Granted
Nobelpharma Co., Ltd. (Head Office: Chuo-ku, Tokyo; President and CEO: Jin Shiomura) received
marketing approval today for RAPALIMUS GEL 0.2% (general name: sirolimus), a drug for the treatment ofangiofibroma in tuberous sclerosis complex.

Tuberous sclerosis is a rare genetic disease that can cause developmental disabilities, and tumor lesions
over the entire body such as in the brain, on the skin, and kidneys. Among those, skin lesions such as
angiofibroma occur frequently, and the symptoms become obvious during adolescence, causing anguish forpatients, and degrading the quality of their lives. However, current treatments are invasive, such as surgery or
laser treatment, which are difficult to administer to young children or patients with developmental disabilities,
and we recognized that no treatment has been given until the condition became serious. That is why a safe,
easy and effective treatment has been sought for many years.

Under these circumstances, the research group of Professor Mari Kaneda of the Department ofDermatology, Course of Integrated Medicine, Graduate School of Medicine of Osaka University, researchedsirolimus, an mTOR inhibitor, as a topical treatment based on the pathology of tuberous sclerosis, andconducted investigator-led clinical trials (phases I and II) with the support of the Ministry of Health, Labourand Welfare Practical Research Project for Rare/Intractable Diseases, the Japan Agency for Medical Researchand Development (AMED), the Department of Pharmacy, Osaka University Hospital, and the Department ofMedical Innovation, Osaka University Hospital, on facial lesions of tuberous sclerosis patients. The trials
showed that sirolimus gel is a safe and extremely effective treatment for the facial angiofibroma of thisdisease. These research results were described in the January 1, 2017 issue of JAMA Dermatology, Volume
153, Number 1 (the Journal of the American Medical Association).

Nobelpharma took the results of this research and conducted a phase III comparative trial and long-term
dosage trial of Rapalimus Gel 0.2% to verify its effectiveness and safety, and in October 2017 became thefirst in the world to apply for marketing approval, and within the short period of less than 6 months obtained
approval of the drug in March 2018.

Rapalimus Gel 0.2% was the first drug to receive the SAKIGAKE designation in October 2015, and thenobtained orphan drug status in December 2015. In the initial developmental stages the national research anddevelopment agency New Energy and Industrial Technology Development Organization（NEDO）provided
support, and in later stages the national research and development agency National Institutes of BiomedicalInnovation, Health and Nutrition provided support.

Rapalimus Gel 0.2% is the only drug with the possibility of local administration to provide treatment offacial angiofibroma from tuberous sclerosis, and it is expected to contribute to the improvement of the qualityof life for patients.

The development of this drug was characterized by 1)the fruits of research by academia, 2)proof of safety
and effectiveness in investigator-led clinical trials, 3)a private company following up on the investigator-led
trials to conduct verification trials, 4)speedy marketing approval in less than 6 months based on theSAKIGAKE designation (particularly the concierge system) and orphan drug designation, 5)extremely good
coordination between industry, government and academia, and 6)in accordance with the SAKIGAKE name,research has now begun overseas as well.

【Contact】
Nobelpharma Co., Ltd.
Kozo Hayase, Head of Administrative Affairs & Corporate Planning
Tel: 03-5651-1160