How to build a rare disease treatment empire for NASDAQ bridgebio in 5 years?

Wen Jie Wang Chan On June 26, 2019, a biopharmaceutical company came out of nowhere, landing on the NASDAQ Exchange of the United States to win the title of the largest biotechnology IPO of the year This company is bridgebio, a rare disease treatment company in the United States It is reported that bridgebio issued 20.5 million shares of common stock on the same day, with a price of $17 per share, and planned to raise $345.5 million The closing price of bridgebio rose by more than 62% to $27.55 per share on the same day On July 1, 2019, the company closed its IPO of common shares The IPO issued a total of 23575000 ordinary shares, including 3.075 million shares sold according to the underwriter's over allotment right exercise, with the actual raised capital of more than $400 million Excluding $28.1 million in discounts and commissions from underwriters and $6.5 million in issuance costs, bridgebio's net income from the IPO was about $366.2 million Bridgebio's success has shown the world a brand-new model for the establishment of biotechnology companies Compared with the traditional model of gathering relevant scientists and investors for certain diseases, bridgebio tends to establish multiple subsidiaries, each of which enjoys semi autonomous operation rights, shares the resources of the parent company and is responsible for the specific business of the parent company According to bridgebio's 2019 annual report, there are 8 wholly-owned biopharmaceutical subsidiaries under the company's name, and 17 companies that actually hold more than 50% shares and have voting rights Bridgebio officials have also said that their business model is more advantageous and efficient than that of other biotech companies Under the support of this mode, the company now has 21 core pipelines, among which 4 pipelines have entered the clinical phase III trial It's worth mentioning that these achievements were made within the five years since bridgebio was founded The company was established in Palo Alto, San Francisco, California in 2015 The company is named "bridge" Its original intention is to build a bridge connecting academic research and clinical application, and to transform the research results of universities, academic medical centers and drug research institutes into gene targeted drugs for clinical treatment "Mendel" is widely known without "Mendel's law of heredity" Behind this is the famous pea hybrid experiment in high school biology textbooks But what people may not know is that there is another kind of genetic disease named "Mendel", which is controlled by an equivalent gene, such as sickle anemia, albinism, color blindness and so on Its single gene variation effect is strong Bridgebio was founded to develop translational medicine for Mendelian genetic diseases, which are rare diseases According to the provisions of the orphan drug act of 1983 in the United States, rare diseases usually refer to diseases with less than 200000 patients each year in the United States (the total population of the United States is about 327.2 million) The drugs used to treat such diseases are called orphan drugs Due to the limited market space of orphan drugs, enterprises expect that the cost of developing such drugs may be difficult to recover from drug sales Therefore, enterprises developing such drugs need to apply for the title of orphan drugs to the FDA of the United States before applying for NDA or bla, so as to obtain economic incentives from the government, such as the opportunity to obtain user fee relief, tax preference, etc At present, bridgebio's drug pipeline awarded the title of orphan drug includes bbp-870, bbp-265, bbp-009, bbp-589, bbp-587 and bbp-631 It is worth mentioning that bridgebio has built more than ten research and development pipelines for Mendelian genetic disease after several years of research on Mendelian genetic disease In addition to the above-mentioned six research and development pipelines awarded the title of orphan drug, bridgebio's research pipelines also include bbp-305, bbp-551, bbp-831, bbp-681, bbp-711, bbp-671, bbp-761, bbp-561, bbp-472, BBP -418 these 10 Part of bridgebio's R & D pipeline (photo from official website) "Every investigational drug in our pipeline representatives hope for an important segment of patients in need of a treatment," bridgebio wrote on its website Indeed, as bridgebio's manifesto States, all of its R & D pipelines are aimed at patients with rare diseases who lack treatment methods, covering molybdenum cofactor deficiency, Gorlin's syndrome, dystrophic epidermolysis (DEB), Leber's congenital AMAD disease, osteoarthritis, venous malformations, PKAN, Leber's hereditary optic nerve There are more than 20 kinds of rare diseases such as pathological changes and PTEN autism Here we focus on the three R & D pipelines that the company has developed into clinical phase III: bbp-870, bbp-265 and bbp-009 Bbp-870 is mainly used for the treatment of type A deficiency of molybdenum cofactor (mocda) It is an extremely rare autosomal recessive congenital metabolic error It is caused by the interruption of the synthesis of molybdenum cofactor (Moco), which is crucial to the activity of sulfite oxidase (SOx) Patients are usually infants or children Mocda can cause irreversible and fatal damage to the nerves of patients, including brain atrophy with white matter necrosis, facial deformity and spastic paraplegia Molybdenum cofactor deficiency (mocd) is characterized by early and rapid progressive postpartum encephalopathy and intractable epilepsy, which eventually leads to severe disability or death The disease is progressing rapidly, with a high infant mortality rate For this rare disease, there is no approved effective treatment to help this part of patients Bbp-870 is an alternative therapy of cyclophosphate monophosphate (CPMP), which aims to reduce the accumulation of toxic sulfites in infants or children with mocd type A, so as to reduce the symptoms of the central nervous system It is worth mentioning that bbp-870 was developed by origin Biosciences, a subsidiary of bridgebio, with the trade name of fostenopterin At present, bbp-870 has already carried out relevant business in Israel, Canada, central and Eastern European countries, and the company is also submitting listing approval application to the US FDA It is reported that bbp-870 has also won the title of "rare pediatric disease" and "breakthrough therapy" in the United States Because the indications of the drug are serious life-threatening diseases, and there is no other alternative therapy at present, bbp-870 is also eligible for the title of priority review If it is approved, it can further speed up the NDA approval time of new drug application review Dr Neil Kirby, CEO of origin Biosciences, a subsidiary, said: "we have started to submit bbp-870 new drug applications for the treatment of mocd a to the US FDA on a rolling basis, which is an important step for our company and patients with diseases We hope that infants with this devastating disease will have quick access to our new therapies " Dr Neil Kumar, CEO of bridgebio, the parent company, added: "bridgebio was founded to develop breakthrough drugs for patients with genetic diseases We hope that the NDA submitted by origin to FDA will become the first batch of products that we seek life changing therapies from patients " Bbp-265 (ag10) is mainly used for the treatment of attr, which is caused by the instability of TTR caused by genetic mutation or aging TTR content can reflect the protein synthesis and content change in vivo after injury Its main function is to maintain the normal level of thyroxine and retinol binding protein (RBP) in human body Under normal physiological conditions, TTR can transport about 15% of thyroxine Attr is usually divided into three categories: wild-type attr cardiomyopathy (attrwt-cm), mutant attr cardiomyopathy (attrm-cm) and attr polyneuropathy (attr-pn) Attr can cause the deposition of amyloid between the cells of various organs in the body, leading to multiple nervous system diseases and cardiomyopathy There is no FDA approved treatment for this disease Ag10 is a TTR stabilizer The drug can stabilize TTR and prevent the formation of toxic amyloid fibrils, so as to achieve the effect of treating attr It is reported that ag10 was developed by Eidos therapeutics, a holding subsidiary of bridgebio Eidos In November 2019, therapeutics published the clinical phase II experimental data of ag10: 41 attr patients received 800 mg of ag10 twice a day After 65 weeks of follow-up, compared with those in the attr study who received placebo treatment, the mortality rate (8.5%) and cardiovascular related hospitalization rate (25.5%) of ag10 phase II participants were lower, and the patients' cardiac biomarkers and echocardiography were also lower The parameters are more stable During the study, 19 participants (40.4%) experienced treatment emergent serious adverse events, of which the most common serious adverse events were congestive heart failure (10.6%) and acute renal injury (8.5%) It is reported that Eidos therapeutics has started the clinical phase III trial of bbp-265, which is expected to start in the first quarter of 2020 Dr Jonathan fox, President and chief medical officer of eidos therapeutics, a subsidiary, said: "the results of the second phase of ag10 clinical trial further prove the continuous tolerance of patients with advanced attr-cm to ag10 The experimental data show that the mortality rate and cardiovascular disease hospitalization rate of patients in the experimental group are significantly lower than those in the control group, which encourages us to continue to support the development of ag10 as a potential best treatment for patients with attr-cm " However, Eidos therapeutics also exclusively licensed bbp-265 to alexion pharmaceuticals, an American pharmaceutical company, for development and commercialization in Japan Its subsidiary, Eidos therapeutics, received US $25 million in advance payment and US $25 million in equity investment In July 2015, bridgebio made an initial investment of $4.5 million in pellepharm, a clinical stage biopharmaceutical company, and in a series of transactions as of December 2016, the company increased its equity to more than 50% Bridgebio determined that it had a variable interest in pellepharm's initial investment, but bridgebio was the main beneficiary until December 2016 Bbp-009 is a small molecule inhibitor (patidigib) of hedgehog signal pathway developed by pellepharm, which is used in Gorlin syndrome and high frequency basal cell carcinoma (BCC), two rare skin cancers PTCH1 gene in patients with Goring's syndrome carries genetic mutation, which leads to the production of multiple BCCs, and most tumors appear in the face At present, there is no FDA approved therapy, and the standard therapy is surgical treatment; high frequency BCC patients are similar to patients with Goering's syndrome, with a large number of BCC on the body surface Unlike Goering's syndrome, high-frequency BCC patients do not carry genetic mutations in PTCH1 gene The current standard treatment for these patients is also surgery Patidigib can inhibit the activation of hedgehog signal pathway by blocking the function of SMO protein, so as to reduce the occurrence of BCC Patidegib's topical gel formulations have shown promising results in phase 2 clinical trials It has been approved by FDA as a breakthrough therapy and orphan drug for the treatment of Goering's syndrome At present, bridgebio is actively providing funds to support pellepharm's phase 3 clinical trial of bbp-009 However, it is worth mentioning that bridgebio's equity control over pellepharm has always been in a dynamic dispute Pellepharm has signed a cooperation agreement with Leo pharma According to bridgebio's assessment, pellepharm is still a vie (variable interest entity) after the reconsideration