Market Place
Data integrity concerns in Japan at Kyowa Hakko; China biotech plant explosion probe
This week, Phispers brings you news on Kyowa Hakko, a Japanese manufacturer of amino acids, which received an FDA warning letter with a recommendation to implement data integrity remediation measures. There is also news on tech billionaires Peter Thiel and Hiroshi “Mickey” Mikitani who are taking new drug developments forward. Meanwhile, Shire won USFDA’s marketing approval for lanadelumab, a monoclonal antibody. This goes on to prove that Takeda’s US$ 62 billion bet of Shire is beginning to pay off. And AstraZeneca’s new inhaler proved worse than its rival from GSK in a clinical trial.
FDA
uncovers data-integrity concerns at Kyowa Hakko in Japan
While patients and regulators across the world deal with the consequences linked to the presence of N-nitrosodimethylamine (NDMA), a probable human carcinogen, as a contaminant in a commonly used blood pressure medicine, valsartan, the inability of multiple inspections by European, American and Chinese regulators to uncover the problem has brought the spotlight back on how regulatory oversight of manufacturing facilities can be improved.
Last week, the FDA posted a warning letter issued to Kyowa Hakko, a leading manufacturer of amino acids and other active pharmaceutical ingredients (APIs) in Japan and recommended that the Japanese firm implement data integrity remediation measures.
This is the second time in the decade that the same Kyowa Hakko site has received a warning letter; the previous one was issued after a 2010 inspection.
In 2010, the FDA investigators cited the failure of Kyowa’s quality control unit/laboratory to thoroughly investigate and document out-of-specification (OOS) results. The 2010 warning letter mentions that Kyowa’s OOS investigations were found to be incompletely documented. Moreover, investigations were not extended to other lots which were impacted by the deviation. Investigations also revealed that certain testing had not been documented and some results could not be located or provided during the FDA inspection.
In the recent inspection performed between September 4 and 8, 2017, the inspectors found the firm had “performed retesting or manipulated data after obtaining out-of-specification (OOS) or other unacceptable results”.
In response to FDA’s recent observations, Kyowa attributed the mishandling of deviations by the firm to its “lack of awareness of the seriousness” of cGMP (current good manufacturing practices) deviations and an “environment where test data could be easily manipulated.”
Kyowa’s controls over its HPLC (high-performance liquid chromatography) systems were found to be inadequate as some HPLC systems did not have the audit trail capability or were not audit trail-enabled. In addition, unique user names and passwords were not required to perform HPLC activities and the personnel used unprotected Excel worksheets to perform calculations and statistical evaluations of production data.
The warning letter also states that FDA cited similar cGMP observations at another Kyowa site during a September 2017 inspection.
Between the warning letters issued in 2010 and 2018, Kyowa’s site located in Hofu-shi, Yamaguchi successfully passed FDA inspections in 2011 and 2014, with the latter resulting in no observations.
After vaccine scandal, China acts on those
responsible for Juxin explosion
On December 9, 2017, an explosion occurred at Lianyungang Juxin Biotechnology Co Ltd in the Lianyungang Chemical Industry Park of Jiangsu Province.
The explosion claimed 10 lives and according to the investigative report by the Jiangsu government, the energy released by the blast was equivalent to 14.15 metric tons of trinitrotoluene (TNT). The blast caused a direct economic loss of 48.7 million yuan (US$ 7 million).
In a crackdown against those responsible for the explosion, the Ministry of Emergency Management under the Chinese government said that the company has been fined 5 million yuan (US$ 730,750). Moreover, its production permit has been revoked and its leaders will be prosecuted.
The report said 45 people and 10 companies were responsible for the blast, and that 13 people will be prosecuted criminally, including Juxin's general manager and production safety director.
According to the report, one of the reasons for the blast was Juxin's failure to ensure its unit’s design and equipment installation complied with legal safety requirements.
The local government of Guannan and its management committee for the chemical industry park were also found not to pay enough attention to safety and the report said it too should be held responsible. The report also found that government departments in charge of safety supervision and project management also failed to perform their duties.
Before the explosion, Lianyungang Juxin had a leading position in the production of pesticide intermediates such as m-dinitrobenzene, m-dichlorobenzene, m-hydroxybenzoic acid and phosphorus pentasulfide.
After its recent crackdown against individuals responsible for the vaccine scandal, China continued action against responsible individuals, within companies and the government, in order to ensure that safety standards are met is likely to significantly impact China’s approach towards manufacturing in the future.
Tech billionaires move innovative new drug developments forward
Tech billionaires Peter Thiel and Hiroshi “Mickey” Mikitani created news last week for taking new drug developments forward.
Japan-born Hiroshi “Mickey” Mikitani founded the Japanese e-commerce giant Rakuten and has an estimated worth of US$ 7 billion.
The story goes back to 2013 when Mikitani’s father was diagnosed with pancreatic cancer.
As he traveled around the world looking for the most advanced treatment methods to cure his father’s sickness, he met Hisataka Kobayashi, a senior investigator at the National Institutes of Health (NIH), who was working on the development of a new cancer treatment called near-infrared photo-immunotherapy (PIT).
PIT focusses on attacking only cancerous cells by chemically joining a monoclonal antibody with a photo-activating dye called “IR700” that is then injected into the bloodstream.
The antibody then traverses the body together with the IR700, finding and “docking” on to the cancer cells.
By locating the docked cells and shining near-infrared light on them, the IR700 undergoes a chemical reaction which pierces the cell membrane, allowing water through the perforation and causing the cancerous cell to expand and rupture in a matter of seconds.
The technology was licensed to Aspyrian Therapeutics in which Mikitani invested and the company is now called Rakuten Aspyrian.
Last week, Rakuten Aspyrian announced it had raised US$ 150 million in a Series C financing. The round, as with previous rounds, was led by Mikitani and brings the company's total fundraising to approximately US$ 238 million in equity.
Tech billionaire Peter Thiel backed COMPASS Pathways received approval from the FDA for a clinical trial of psilocybin therapy for treatment-resistant depression.
Psilocybin is a naturally occurring psychedelic prodrug compound produced by more than 200 species of mushrooms, collectively known as psilocybin mushrooms or “magic mushrooms”.
This FDA approval follows approval of Epidiolex (cannabidiol or CBD), an active ingredient obtained from marijuana, for the treatment of seizures associated with two rare and severe forms of epilepsy.
The trial will be a phase IIb dose-ranging study with 216 patients taking part in 12 to 15 research sites across Europe and North America. Regulatory approvals for the trial have already been given in the UK, the Netherlands and Canada.
Takeda’s bet on Shire begins to pay off; key drug bags FDA approval
Just a few months after Takeda announced its US$ 62 billion acquisition of Dublin-based Shire, the Irish drug company got FDA’s marketing approval for lanadelumab – a monoclonal antibody that showed outstanding phase III results for a rare hereditary disease following a priority review by the agency.
Lanadelumab is a treatment designed for patients aged 12 and above with hereditary angioedema (HAE) — a rare disease affecting one in 50,000 men and women with symptoms such as recurrent, unpredictable episodes of severe swelling, most often in the stomach, limbs, face and throat.
In a pivotal 26-week Phase III clinical trial, the HELP (Hereditary Angioedema Long-term Prophylaxis) Study, which included 125 patients, 27 patients receiving 300 mg lanadelumab once in every two weeks saw an 87 percent reduction in the number of monthly HAE attacks when compared with a placebo. A little less than half the patients who received 300 mg of the Shire drug every two weeks had zero HAE attacks compared to the placebo.
Analysts expect the drug to bring in US$ 1.3 billion and Takhzyro dominated a chart put together by GlobalData on the future sales potential for Shire’s product pipeline.
The FDA also approved European pharmaceutical company, Dompé farmaceutici SpA’s treatment for neurotrophic keratitis — a rare and progressive eye disease which can lead to corneal scarring and vision loss.
The ophthalmic solution, Oxervate (cenegermin-bkbj), is a recombinant human nerve growth factor (rhNGF) that resembles the nerve growth factor of the human body and acts directly on corneal epithelial cells to stimulate their growth and survival.
The regenerative potential of NGF was discovered by Nobel-prize winning scientists, but its therapeutic potential was not realized in ophthalmology until Dompé's research and development team based in L'Aquila, Italy, created cenegermin-bkbj, a recombinant version of the human NGF, through a unique development process.
Oxervate’s approval from the FDA came a year after it won a nod in Europe. Dompé plans to roll out the drug in early 2019, according to sources quoted by FiercePharma.
Neurotrophic keratitis has an incidence rate of five in 10,000 individuals.
AstraZeneca’s new inhaler fails to match GSK’s drug in a clinical trial
AstraZeneca’s new inhaler Bevespi Aerosphere (glycopyrronium/formoterol fumarate) for chronic lung disease posted disappointing results last week as it proved worse than rival GlaxoSmithKline’s product Anoro Ellipta (umeclidinium/vilanterol) in a clinical trial.
AstraZeneca said the results were inconsistent with earlier findings as it waits for European authorities to approve the inhaler later this year.
The study found that Bevespi Aerosphere was as good as GSK’s product in improving peak breathing levels when patients exhaled, but it failed to match Anoro on trough measures.
Both drugs were already FDA-approved and are on the market for chronic obstructive pulmonary disease (COPD). GSK’s Anoro Ellipta was approved by the FDA in December 2013 and generated US$ 482 million in sales, while AstraZeneca’s Bevespi Aerosphere obtained an approval in April 2016 and had sales of only US$ 16 million.
COPD is a huge space within respiratory diseases, globally affecting about 384 million people.
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