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- 2026-04-11 18:25:00
- Policy
- Janssen's Talquetamab, approved for Phase 3 in Korea
- by Lee, Hye-Kyung Sep 28, 2022 06:05am
- While Janssen's Talquetamab is undergoing phase 3 clinical trials around the world, phase 3 approval has been granted to 44 patients in Korea. On the 26th, the Ministry of Food and Drug Safety approved the Talquetamab subcutaneous injection and Daratumumab subcutaneous injection (Tal-DP) or Daratumumab subcutaneous injection and Daratumumab subcutaneous injection (Dalatum-3) in clinical trial subjects with at least 1st prior therapy. Currently, multinational clinical trials are underway for patients with recurrent or refractory multiple myeloma, and the total number of clinical trials is 810. In Korea, clinical trials will be conducted at Severance Hospital, Samsung Medical Center, Hwasun Chonnam National University Hospital, Seoul St. Mary's Hospital, Seoul Asan Medical Center, Seoul National Cancer Center, Gil Hospital, Chonbuk National University Hospital, and Dong-A University Hospital. A double antibody is an antibody that simultaneously recognizes two different antigens. Treatments are characterized by targeting both factors that cause disease. For example, it can act on immune cells and cancer cells at the same time to catch two rabbits, strengthening immunity and attacking cancer cells. Representative double-antibody anticancer drugs include Amgen's acute leukemia treatment BLINCYTO (Blinatumomab) and Roche's hemophilia type A treatment HEMLIBRA (Emishzumab). Talquetamab targets both GPRC5D and CD3 of T cells, a new multiple myeloma target, with off the shelf T cell-redirecting double antibody. According to data released by ASCO last year by Janssen, subcutaneous administration of phase 2 recommended doses in 30 patients with recurrent or refractory multiple myeloma with a median value of 6 months or more was 70%, and 60% of patients achieved VGPR (very good partial response). Subjects of clinical trials previously received the sixth treatment at a median value, and 87% did not respond to the last treatment. Reactions were observed in 70% of patients, including 65% of patients who were non-responsive to three drugs and 83% of patients who were non-responsive to five drugs, and during the 6.3 months of the follow-up period, patients have not yet reached the median of the response period.
- Company
- Reduce steroid in long-term use of Dupixent in asthmatic pts
- by Sep 28, 2022 06:05am
- Sanofi's Dupixent was found to improve major symptoms in a three-year long-term follow-up of severe asthma patients while reducing the use of oral corticosteroids. The results of these studies were released at the 2022 ERS Annual Academic Conference held from the 4th to the 6th. Through this conference, Dupixent released a number of data and RWE data confirming the improvement effect of asthma symptoms related to type 2 inflammatory biomarkers to solidify the treatment effect and safety profile in type 2 inflammatory severe asthma. It proved that it is a treatment that reduces the frequency of deterioration of severe asthma and lowers the severity, thereby helping to reach the treatment goal of severe asthma. Post-analysis study data from VENTURE/TRAVERSE clinical trials once again suggested that Dupixent could be a treatment solution for severe asthma patients, including Steroid-dependent patients. According to published data, Dupixent reduced steroid use for three years while improving major symptoms of asthma, including severe annual exacerbation and lung function deterioration. The results of this post-analysis study were conducted on Steroid-dependent asthma patients who participated in the VENTURE study, the existing phase 3 clinical trial of Dupixent. Patients who were administered Dupixent 300 mg or placebo every two weeks in the existing VENTURE clinical trial received additional Dupixent for up to 96 weeks through TRAVERSE clinical trials. These patients were analyzed by dividing them into patients who used Steroids less than or equal to 10 mg per day. If the daily usage exceeds 10 mg, caution is needed as it can be exposed to steroid side effects such as diabetes and osteoporosis in the long run. According to the main results, Dupixent decreased the annual severe asthma exacerbation rate of patients regardless of Steroid use at 96 weeks from the end of the previous study, VEUNTURE. Among patients with daily Steroid use exceeding 10 mg, the placebo-administered group showed an improvement of more than 81% in the annual severe asthma exacerbation rate at 96 weeks of Dupixent administration. It was also found to have improved by more than 43% in the existing Dupixent administration group, confirming the effect of Dupixent in Steroid-dependent asthma patients. In the group of patients with daily steroid use of 10mg or less, it was found to have improved by more than 80% and 36%, respectively, compared to the baseline of the VENTURE study. Steroid use also decreased as asthma symptoms improved with Dupixent. Dupixent reduced Steroid use by more than 70% at 96 weeks of administration, regardless of both Dupixent/ placebo administration and Steroid use compared to the baseline of the VENTURE study. Patients with daily steroid use exceeding 10 mg also decreased by 83%, confirming the long-term treatment effect of Dupixent in Steroid-dependent patients. The data released on that day also included RWE data from the United States analyzed for severe asthma patients who received Dupixent. According to the data, Dupixent reduced the rate of emergency room visits related to asthma by up to 73.4%, and the rate of hospitalization by up to 66.7%. In addition, it has been confirmed that medical expenses related to asthma have been reduced by reducing the frequency of visits to internal medicine.
- Policy
- Generic for Acelex will be released
- by Lee, Tak-Sun Sep 27, 2022 05:51am
- A new domestic anti-inflammatory drug developed by Crystal Life Science Generic drugs of the domestic anti-inflammatory drug Acelex developed by Crystal Life Science will be on the market from next month. It has been seven years since Acelex was licensed in Korea, and attention is being paid to whether generic, like the original, will be able to expand its market. This is because Celecoxib has high market dominance among coxib families. According to industries on the 26th, eight Acelex generics will be listed on the 1st of next month. Generic companies are Daewoong Pharmaceutical, Hutecs, Ilhwa, CrystalLife Science, Kuhil, Edenpharma, CMG Pharma, and Hana. Except for Daewoong Pharmaceutical, seven items will receive an additional amount of 522 won for one year, including first generics, and will be adjusted to 470 won on October 1 next year. Daewoong will be listed at 597 won, but will also be adjusted to 470 won on October 1 next year. Generic is in competition with original, but Acelex generic is in partnership with original. This is because Crystal Life Science, an affiliate of Crystal Genomics, produces products like the original company. Therefore, the original company's production performance will expand only when generic sales increase. Original and generic market expansion, by having common goals. Cerebrex 400 billion won in annual performance record. 2016, patent expiration as a generic is reimbursed. Acelex is properly lost the use of force and with earnings of less than 10 billion won per year. The sluggishness of Arcoxia and Acelex is due to the fact that the indication is limited to osteoarthritis and that the marketing ability was not great to destroy Cebrex's position. Since large companies such as Daewoong Pharmaceutical are included in Acelex generics this time, generics are expected to expand the overall market size, allowing both original and generics to create synergy.
- Company
- MOHW's view of ‘few’ and ‘pediatric’ for PE exemptions
- by Eo, Yun-Ho Sep 27, 2022 05:51am
- Chang-Hyun Oh, Director of Pharmaceutical Benefits at the Ministry of Health and Welfare Although yet to be finalized, the PE exemption criteria will not be amended' in the direction desired by pharmaceutical companies. In particular, companies are likely to have little room in utilizing the special exemption of the pharmacoeconomic evaluation system due to the restrictions set, such as treatments that are used by ‘few’ patients and those with ‘pediatric’ indications. The period for industry opinion collection still remains, with the deadline being the 30th. But as the government is determined to implement the amendments to the system, to what extent the opinions will be reflected remains to be seen. Chang-Hyun Oh, Director of Pharmaceutical Benefits at the Ministry of Health and Welfare, said so regarding the “Measures to Improve Patient Access and Manage Reimbursement of High-Priced Severe Disease Treatments" at a recent meeting with the multinational pharmaceutical company press gallery. The ‘Few’ patients standard to be maintained at a 200-patient level The government's improvement plan raised industry concerns because it changes the major premise set for PE exemptions. The new change adds ‘few numbers of subject patients’ as a prerequisite for PE exemptions. Originally, the condition was a ‘OR’ clause included with other optional clauses such as ‘if a single-arm study was conducted,’ under Subparagraph 2(c) of Regulation for Drugs Subject to PE Exemptions. The ‘few’ was defined to be in the 200 range. Although the exact number has not been specified in the condition, the PE exemption evaluations has been made at that level. Therefore, there were many opinions in the industry that the number defined as a ‘few’ should be adjusted upward if the condition was to become a prerequisite. However, Director Oh said, “We don’t plan to change the standards we set to define the ‘few’ just because of the amendment. However, no specific number is universally applied to all drugs, therefore, the number may be flexibly adjusted to a small extent for each drug in the future." In other words, if the amendment is applied as is, all drugs that seek PE exemptions will first have to satisfy the 'few numbers of patient' (around 200) requirement, then receive recognition from the committee for their difficulty to generate PE data. What about drugs that have broader indications that are applied to pediatric to adult patients? The main point of the system improvement being made was to improve coverage for pediatric patients. The government had added the clause 'drugs used to treat pediatric patients that are therapeutically equivalent or has no available treatment option, and demonstrates improvement in quality of life or is otherwise approved by the committee.' In essence, the added clause excluded the 'life-threatening disease' condition for PE exemptions just for pediatric patients. In other words, if drugs used for pediatric patients satisfy the remaining conditions, the PE exemption may be applied even if the condition is not life-threatening. On the surface, it seems like an encouraging improvement. However, there were wild speculations in the industry on what the scope of 'drugs used in pediatric patients' will be. The government had not specified whether the 'drugs used to treat pediatric patients' clause applies only to diseases that occur only in children, drugs that only have indications for children, or drugs that can be prescribed broadly to children and adults. However, it is likely that this clause will also not be widely applied. Director Oh said, “It is difficult to provide a clear answer on that part. However, the system was not intended to limit the indication of drugs that can be used for even the adults to only children so that they can take the PE exemption track."
- Policy
- Hutecs targets pitavastatin market with its lowest-price
- by Lee, Tak-Sun Sep 27, 2022 05:51am
- Hutecs Head Office in Hwaseong City Hutecs Korea Pharmaceutical throws a winning bid in the hyperlipidemia treatment pitavastatin market represented by the original drug Livalo. As the 21st latecomer introduced to the market, Hutecs’ generic is putting pressure on other competitor companies, being listed at a price lower than 85% of the current lowest price. According to industry sources on the 26th, Hutecs succeeded in listing both Lovalow 1mg and Lovalow 4mg with reimbursement. The ceiling price was set at KRW 295 for the Lovalow 1mg, and KRW 527 for Lovalow 4mg. The two products are both listed at the lowest price among the listed products. In particular, the price of Lovalow 4mg was set 28% lower than the current lowest price (KRW 715). Lovalow 4mg is the 21st product to be listed. Under the drug pricing regulations, from the 21st generic listed in the system, the price is set at 85% of the lowest price. However, the price of Lovalow 4mg was set even lower. With the listing, the ceiling price of the already listed Lovalow 2mg will also inevitably be discounted. This is because when a product from the same company with an identical route of administration, ingredient, and formulation, but with a different strength is already listed, the ceiling price of the lower strength is adjusted to be lower than that of the higher strength under regulations. Therefore, the price of Lovalow 2mg was lowered to KRW516 from KRW561. This is KRW 1 lower than that of Lovalow 4mg. As a result, Lovalow 2mg, which was the lowest priced product among the same ingredient drugs, is expected to become the second lowest priced product. Competition in the pitavastatin market is fiercer for the 2mg products. A total of 48 same ingredient products are competing in the market. With its 1mg and 4mg formulations being listed later in the market, Hutex seems to be throwing in the winning bid and extending its price competitiveness to the 2mg formulation market as well. Pitavastatin is a steady seller that has been long beloved in the hyperlipidemia treatment market. Its original, Livalo, had recorded KRW 79.7 billion (Data: UBIST) in outpatient prescriptions last year.
- Company
- Daewoong Nabota is expected to take a global leap
- by Nho, Byung Chul Sep 27, 2022 05:51am
- As Daewoong Pharmaceutical's botulinum toxin product Nabota (Jubo·Jeubeau) is likely to surpass 100 billion won in sales this year, it is drawing attention as it is expanding its global scope as a representative K-toxin product. Nabota, which was launched in Korea in 2014, recorded 15.1 billion won in 2019 It achieved sales of 79.6 billion won last year after Quantum Jump, 233% sales of 50.4 billion won the following year. After the FDA approved the final item license in February 2019, it began to target the North American market in May of the same year. The U.S. occupies 50% of the global toxin market worth 6 trillion won, and Allergan Botox products are leading the treatment, beauty, and plastic surgery market. Europe is the second-largest market for toxin drugs, and Nabota is expected to be launched in the second half of this year. Item licenses in China, which are highly regarded for its rapid growth and potential market value, are also expected to be approved as early as this year, and full-fledged releases and profits are expected from next year. Evolus is in charge of the beauty business partners in the U.S., Europe, Australia, and Canada, while Ion Biopharma is in charge of the treatment business partners in the U.S. Currently, Nabota is in charge of production at the first plant of Hyangnam Pharmaceutical Complex, and when the second plant is completed in 2025, it is expected to become a global leading company as it can produce a total of 5 million vials per year. As of September 2022, Nabota's indications include eyelid wrinkles, eye wrinkles (abnormal beauty), improvement of upper extremity muscle stiffness after stroke, and eyelid cramps (abnormal treatment). As for the progress of additional indications, it is waiting for approval after submitting approval to the MFDS in April 2022 for the world's first item permission to add positive adiabatic hypertrophy (square jaw improvement). In addition, phase 2 clinical trials for chronic and inflammatory migraine and cervical muscle tension are underway in the United States, Canada, and Australia. A panoramic view of Nabota Chronic migraine headaches account for 40% of the total treatment market, and there is no competition other than Botox yet. If Nabota enters this field, it is expected to penetrate the market quickly based on price competitiveness.I t is also preparing clinical trials for gastric paralysis indications, which do not yet have a clear treatment. It is predicted that a new treatment paradigm can be provided in a unique way by injecting toxin directly into the upper and lower parts of the stomach through endoscopy. In addition to the three global toxin markets, plans to release them in niche markets such as Turkey, Chile, Peru, Saudi Arabia, Egypt, and Indonesia are also drawing attention. Nabota is a premium toxin brand based on high-pure technology patent technology. An official from Daewoong Pharmaceutical said, "Nabota is the only product in Asia that has been approved for sales in the United States, Europe, and Canada." "We plan to expand our markets in the U.S., Europe, and China through aggressive investment in the future," he said. Meanwhile, Nabota's ITC lawsuit disappeared in February last year when Daewoong Pharmaceutical's U.S. partner Evolus signed a three-way agreement with AbbVie and Medy Tox, and has since grown rapidly based on U.S. exports. Of Nabota's overseas sales in the second quarter, exports to the U.S. through Evolus amounted to 21.1 billion won, which doubled from the same period last year.
- Company
- 4 pharmaceutical companies challenge to add Vemlidy patents
- by Kim, Jin-Gu Sep 27, 2022 05:51am
- VemlidyGilead Sciences' patent for hepatitis B treatment Vemlidy (Tenofovir) is increasing. While Dong-A ST, Daewoong Pharmaceutical, Chong Kun Dang, and Jeil succeeded in avoiding patents for the first time in March this year, Samjin, Hutechs, DongKook, and Samil have challenged the same patent for the past two months in a row. According to the pharmaceutical industry on the 23rd, Samil recently requested a passive judgment on the scope of rights for the Gilead Vemlidy salt patent. Since Samjin challenged the same patent in July, a total of four companies, including Hutechs and DongKook, have joined patent disputes in the past two months. This patent has already been successfully avoided by Dong-AST, Daewoong, Chong Kun Dang, and Jeil in March this year. Samjin, Hutechs, DongKook, and Samil challenged the same patent as generics. The background of a series of generic challenges is that there is no impact on generic exclusivity. The drug is an upgraded version of Gilead's existing hepatitis B treatment Viread. However, since the main ingredient is Tenofovir, generic for Vemlidy is not given a separate opportunity to acquire generic exclusivity. Gilead developed a new Vemlidy in the form of pro-drug. Through this, drug resistance and renal toxicity side effects have been improved. Vemlidy is rapidly replacing the existing Viread in the hepatitis B treatment market. According to IQVIA, a pharmaceutical market research firm, sales of Vemlidy surged in four years from 500 million won in 2017, the first year of its launch, to 28 billion won last year. During the same period, Vemlidy's sales nearly halved from 129.3 billion won to 63.1 billion won.
- Policy
- MFDS in discord regarding promotion of oral COVID-19 Txs
- by Sep 26, 2022 06:08am
- The government is encouraging the use of oral COVID-19 treatments in high-risk groups, however, accessibility to such has been limited for healthcare professionals due to limitations in emergency use approvals. The Ministry of Food and Drug Safety is being criticized for being passive in making legal interpretations for emergency use authorized drugs, which is in discord with the government’s disease control and prevention measures. According to industry sources on the 26th, pharmaceutical companies are disallowed from conducting academic marketing for their oral COVID-19 treatments as the subject drugs were approved under Emergency Use Authorizations. Usually, when new drugs are released, companies conduct various activities to raise awareness of the drugs, making visits to hospitals to explain their drugs and holding webinars or symposiums to provide educational material. The new drugs in the market can only be actively used after the healthcare professionals gain a better understanding of the drugs and accumulate prescription experience. However, as COVID-19 treatments were granted emergency use according to the Special Act on the Promotion of Development and Urgent Supply of Medical Products in Response to Public Health Crisis, the authorities deemed that the drug are not allowed the advertising privileges granted under the Pharmaceutical Affairs Act. According to Article 68-5 of the Pharmaceutical Affairs Act, the imported pharmaceutical product’s name, manufacture method, and efficacy cannot be advertised unless the drug product has been approved or reported according to Article 42-1 of the Pharmaceutical Affairs Act. As drugs granted Emergency Use Authorization was not approved under Article 42-1 of the Pharmaceutical Affairs Act, the MFDS’s interpretation was that such drugs are not allowed to conduct advertisements. Due to this, the government is solely in charge of providing the necessary information on oral COVID-19 treatments in Korea. The Korea Disease Control and Prevention Agency is in charge of training healthcare professionals to provide medication guidance to patients, etc. However, it has been pointed out that the government’s education sessions are not enough to cover the expanded scope of institutions and pharmacies approved to prescribe and dispense oral COVID-19 treatments. Also, the participation rate, frequency, and effect of KDCA’s education sessions are relatively lower than that of pharmaceutical companies due to lack of promotions among other reasons. There are also opinions that more explanation is needed because the sessions are not carried out by medical professionals. Many healthcare professionals and pharmacists who still have not received a prescription or medication guidance yet have reported experiencing confusion. However still, officials of pharmaceutical companies that can communicate most closely with healthcare professionals have been passive in dealing with the issue due to concerns about violating the Pharmaceutical Affairs Act. As an active explanation of the drugs was prohibited, the officials can only respond when receiving inquiries from healthcare professionals. This is why the prescription rate has not risen much even though the government has greatly expanded the number of institutions that can prescribe oral COVID-19 treatments. According to the Central Disaster and Safety Countermeasure Headquarters (CDSCH), the prescription rate of oral COVID-19 treatments in those over the age of 60 as of the 2nd week of September, remained at 27%. The prescription rate has more than doubled in 4 months with the encouragement of the disease control and prevention authorities, but the government believes it is necessary to further increase the prescription rate. The importance of prescribing oral treatments has risen after the prescriptions had significantly reduced the progression to severe disease in patients in the high-risk group over the age of 60 during the COVID-19 outbreak last summer. The CDSCH’s analysis of its disease control progress and response to the resurge of COVID-19 in the summer showed that the progression to severe disease decreased as the prescription rate for oral COVID-19 treatments increased for those aged 60 years or older. The rate of progression to severe disease, which had been 1.28% in February when the administrate rate was 6.4%, dropped to 0.42% with the rise of the administration rate to 21.7% in August. The disease control and prevention authorities are also busy preparing measures to address the issue of prescriptions being limited due to a lack of clinical information in the field. According to the 'Measures to Raise Prescriptions of Oral COVID-19 Treatments’ that had been reported by CDSCH last month, healthcare professionals were reluctant to prescribe oral COVID-19 treatments due to a large number of contraindicated drugs and lack of clinical information. Accordingly, the authorities are contemplating ways to increase accessibility to information by preparing educational materials and prescription guidelines. To address the continued criticism over the limitations in information, the authorities recently partially granted pharmaceutical companies to produce and distribute materials containing drug information. As such partial activities have clear limitations, voices for proactive allowance of pharmaceutical companies to conduct academic marketing on EUA drugs have also been rising. Contrary to the government's stance, the MFDS had been passive in making legal judgments regarding EUA drugs. At the time of introductions, pharmaceutical companies had made several inquires to the MFDS on what scope of information provision activities is allowed for their drugs. At the time, the MFDS only responded that “It is difficult for the ministry to provide a definite answer due to lack of information in determining the necessity and validity of providing information." The pharmaceutical companies received the response as a “don’t.” Regarding this, the MFDS said, “The COVID-19 treatments that were granted EUA are directly managed by the KDCA, and the KDCA has been providing various information for healthcare professionals and patients. We will consult with the department in charge to see if academic marketing is allowed." The Advisory Committee on Infectious Diseases also agrees on the need for the government to make proactive decisions and improve and expand healthcare professionals’ accessibility to information. During a phone interview with Dailypharm, Gi-Seok Jeong, Director-General of Special Response of the Central Disaster and Safety Countermeasure Headquarters, said, “Despite the state’s efforts in encouraging the prescription of oral COVID-19 there are still many cases in which prescriptions are not available to patients who need them in the medical field. Adding pharmaceutical companies' information provision activities to the effort will help increase the prescription rate. It seems necessary that the government should take active action to overcome obstacles that may hinder engagement in such activities that would lead to an increase in the prescription rate, by requesting authoritative interpretation from the Ministry of Government Legislation.”
- Company
- Praluent can be prescribed at general hospitals
- by Eo, Yun-Ho Sep 26, 2022 06:08am
- PCSK9 inhibitor Praluent has settled on general hospitals. After registering insurance benefits in June 2021, the landing process is steadily underway. According to related industries, Sanofi-Aventis Korea's Praluent passed the Pharmaceutical Affairs Committee (DC), including Samsung Medical Center, Asan Medical Center, Sinchon Severance Hospital, Bundang Seoul National University Hospital, Chonnam National University Hospital, and Pusan National University Hospital. The drug was approved in Korea in January 2017, but was listed last year. Amgen Korea's Repatha, which was approved around the same time, was first registered as a Homozygous Family Hypercholesterolemia (HOFH) indication in August 2018. In other words, there were two PCSK9 inhibitors, but in fact, Repatha was the only option. Since last year's salary registration, Sanofi has carried out the landing process at general hospitals, and as it has shown results this year, the competition between the two drugs is expected to begin in earnest. In January 2020, Repatha succeeded in expanding the criteria for high-risk patients with atherosclerotic cardiovascular disease (ASCVD), heterozygous family hypercholesterolemia (HeFH), and non-heterozygous patients. It is believed that the actual battlefield between the two drugs will also be the ASCVD and HeFH regions. Praluent added a HoFH indication in the United States in April last year. Praluent has a tendency to reduce the risk of all-cause death, and it has the advantage of being able to select patient-specific doses by referring to patient status and LDL-C levels as two approved drugs, Praluent 75 mg and Praluent 150 mg. Meanwhile, MSD is currently developing oral PCSK9 inhibitor. MSD announced phase 1 clinical results of the candidate substance MK-0616 at the American Heart Association (AHA) conference last year. Studies have shown that up to MK-0616 300 mg was administered to healthy men, or LDL cholesterol was reduced without serious side effects or death when administered with Statins in men and women with high cholesterol.
- Company
- The anesthetic drug Byfavo is available in general hospitals
- by Eo, Yun-Ho Sep 26, 2022 06:08am
- Byfavo, the first anesthetic drug in 30 years, has settled on a general hospital prescription. According to related industries, Hana Pharmaceutical's Byfavo passed the Drug Commission (DC) of Big 5 General Hospitals, including Seoul National University Hospital, Asan Medical Center, and Sinchon Severance Hospital. Byfavo is a new anesthetic drug released more than 30 years after the approval of the frequency prescription general anesthetic Propofol. Byfavo, which was launched in March, secured manufacturing rights and exclusive sales rights from Germany's Paion in 2013. Since 2018, phase 3 clinical trials have been completed for 198 subjects who perform general anesthesia in Korea. The main indication is inducing and maintaining general anesthesia in adults. Byfavo is a pure anesthetic new drug that has no analgesic effect, and has pharmacological and pharmacological advantages of existing general anesthetics such as Propofol and Midazolam. Hana is under construction with German freeze-drying facilities through its new Hagi plant, which is expected to operate in 2023, and designed to supply Byfavo to advanced markets. In addition, it acquired additional copyrights to Byfavo in six Southeast Asian countries from the original developer Paion in Germany, and completed all internal work to receive permission documents in these countries
