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DMF submissions in 2019: India maintains bulk drug supply supremacy to US

At PharmaCompass, we highlighted the significance of India in the global active pharmaceutical ingredient (API) supply chain last week with our list of generic drug facilities registered with the US Food and Drug Administration (FDA). Our compilation revealed that India had 182 generic drug facilities registered with the FDA and this number was nearly as much as the corresponding numbers for China (100) and United States (84) put together. These 182 facilities paid a fee of US$ 59,400 each to the FDA. View FDA DMF Filings in 2019 (Power BI Dashboard, Free Excel Available) This week, we review the API Drug Master Files (DMFs) submitted to the FDA in 2019. Expectedly, India also led the DMF submission list. In 2019, there were 616 active DMF submissions to the FDA with Indian companies submitting more than half (331) of them. Submissions from India were a little less than double the number of DMF submissions made by Chinese (113) and the US (57) firms put together. Drug master files (DMFs) are submissions made to the FDA by manufacturers by providing the agency with confidential, detailed information about facilities, processes, or articles used in manufacturing, processing, packaging, and storing of human drug products. View FDA DMF Filings in 2019 (Power BI Dashboard, Free Excel Available) MSN Labs leads total count of DMF filings The 616 active DMF filings to the FDA were quite diverse — they covered over 400 products, and over half (322) the filings were for unique products. Among the products with multiple DMF filings, Sugammadex Sodium topped the list as it had 18 DMF filings. Sugammadex is the API used in Merck’s Bridion for the reversal of neuromuscular blockade induced by rocuronium and vecuronium in general anesthesia. The other products with over five DMF filings were for the APIs of Lundbeck and Otsuka’s antipsychotic drug Brexpiprazole, Novartis, Gilead and Intercept’s blockbuster products Sacubitril-Valsartan, Tenofovir Alafenamide Fumarate and Obeticholic Acid. View FDA DMF Filings in 2019 (Power BI Dashboard, Free Excel Available) The year 2019 also witnessed continued DMF filings for Rivaroxaban, Sitagliptin Phosphate, Ticagrelor and Tipiracil Hydrochloride. These filings indicate that the companies currently developing these products should brace themselves for intense competition in the near future. India’s MSN Labs continued to lead the count of total DMF filings with 42, of which it had 17 filings where it was the only one submitting a DMF for a specific product in 2019. The leading Chinese company filing DMFs was Fuxin Long Rui Pharmaceutical with nine DMFs, followed by Brightgene Bio-Medical Technology Co with five. The API DMF is part of the final generic drug product submission to the FDA. Therefore, the owner of a DMF incurs a one-time fee (US$ 55,013 for FY2019, US$ 57, 795 for FY2020) the first time the generic drug submission references that DMF. View FDA DMF Filings in 2019 (Power BI Dashboard, Free Excel Available) DMF holders may also pay the fee in advance in order to have their DMF subjected to an initial completeness assessment by the FDA. This would allow their DMF to be included on a publicly-available list of DMFs that have paid their fee and not failed the initial completeness assessment. Aurobindo, Sun, Lupin lead DMF assessments While reviewing the DMF submissions made in 2019, we found that a third (209 out of 621) of the DMFs were listed on FDA’s publicly-available list of DMFs that have paid their fee and whose initial assessment had been completed. This indicates that either companies may have been unwilling to pay the fee or the FDA’s review process found shortcomings in their applications. Major Indian generic drug companies like Aurobindo (16), Sun Pharmaceuticals (13), MSN Labs (12), Lupin (7) and Macleods (7) led the list of companies that had the maximum DMF assessments completed for their 2019 submissions. There are also DMF submissions for products which can sometimes indicate future drug approvals. View FDA DMF Filings in 2019 (Power BI Dashboard, Free Excel Available) Sanyo Chemicals submitted a DMF for Ibudilast, an anti-inflammatory drug whose oral capsules are used in Japan for the treatment of asthma and its ophthalmic solution is used to treat allergic conjunctivitis. The product is currently not approved in the United States. New drug approvals in the future can also be expected for Tertomotide, Omarigliptin, Estetrol Monohydrate, Abametapir, Pirenzepine, Cortexolone Proprionate, Lurbinectedin, Terlipressin, Ethyl Olivetolate, Remimazolam and Triapine. These products are currently under clinical trials for a variety of indications. Our view After compiling the list of companies that have submitted DMFs to the FDA as well as the generic facilities that paid their user fees, it’s clear that the API industry is beginning to find a new equilibrium. View FDA DMF Filings in 2019 (Power BI Dashboard, Free Excel Available) Our compilations of the previous years have shown that there is a steady decline in facility registrations and DMF filings. Given the increasing costs involved, as well as scaled up regulatory requirements, it seems that companies are becoming more selective in their product development decisions and also their willingness to do business in the United States. While the number of Indian API facilities registered with the FDA has remained relatively unchanged, the number of Chinese sites that registered with the US has reduced by 35 percent over the past five years. Several factors are changing the landscape of the generic drug industry. For instance, environmental regulations in China are driving up the cost of raw materials. Quality issues — such as the valsartan impurities case — have increased regulatory scrutiny. Moreover, passing inspections continues to remain a challenge for many manufacturers. And generic drug product manufacturers are also facing margin pressures, which in turn is driving a lot of M&A activity. Given this scenario, the generic industry should brace itself for more challenges in 2020. View FDA DMF Filings in 2019 (Power BI Dashboard, Free Excel Available)

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23 Jan 2020

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Axovant’s hyped Alzheimer’s drug fails trial as Pfizer emulates Axovant; Amneal and Impax in merger talks

This week in Phispers, we bring you news about intepirdine, Axovant’s experimental drug for Alzheimer’s disease, on which both patients and investors had vested much faith. The drug failed primary endpoints. Meanwhile, Pfizer is emulating the Axovant strategy as it split four of its clinical-stage orphan drugs into a new company. There was more bad news for Biocon-Mylan, as Amgen filed a patent infringement case against Mylan in the US. Novartis’ new CEO says it will reduce the development cost of drugs by relying on data science. And, there is news on NASH drugs and on merger talks between Amneal and Impax Labs. Axovant disappoints investors; its Alzheimer’s drug fails primary endpoints After two years of brouhaha by investors, Axovant’s experimental drug intepirdine, as a treatment for mild to moderate Alzheimer’s disease, turned out to be a damp squib. The experimental drug did not meet its co-primary efficacy endpoints, a press release issued by Axovant said. The medicine turned out to be no different from 99 percent of medicines tested against Alzheimer’s. Investors had poured millions of dollars into Axovant. According to an estimate compiled by Bloomberg, intepirdine was expected to generate more than US$ 2 billion in sales for Axovant by 2023. But that was not to be. At 24 weeks, patients treated with 35 mg of intepirdine did not improve on either of two surveys — the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL) — compared to patients treated with placebo. Back in 2015, Axovant — a company founded by Vivek Ramaswamy — had bought intepirdine from GlaxoSmithKline for US$ 5 million and launched Axovant’s US$ 315 million IPO around the drug. That’s when PharmaCompass had raised the question — has 29 year-old Ramaswamy shown GlaxoSmithKline that it made a billion dollar mistake by selling of its old Alzheimer drug to him? In April this year, Ramaswamy stepped down as CEO of Axovant by appointing former chief executive of Medivation, David Hung, in his place. Medivation got sold to Pfizer for US$ 14.3 billion last year. Last month, Ramaswamy’s Roivant (Axovant’s biggest shareholder) raised US$ 1.1 billion from big investors lead by Softbank’s Vision Fund. Roivant also raised millions of dollars from hedge funds like Viking Global Investors. These investments diluted the stakes of Ramaswamy and other initial investors in Roivant. But Ramaswamy is laughing all the way to the bank. Through divestments, he has secured a war chest for Roivant, which has been spinning out new companies with names ending with ‘vant’ — such as Axovant (neurology), Myovant (women's health and endocrine diseases), Dermavant (dermatology), Enzyvant (rare diseases), and Urovant (urology). Pfizer emulates Axovant; Ibrance maybe a US$ 5 billion drug next year Even as Axovant’s intepirdine failed to meet primary endpoints, the American pharmaceutical behemoth Pfizer seems to have taken a leaf out of its strategy book. Pfizer’s R&D strategy executive Lara Sullivan gained the company’s support to split four of its clinical-stage orphans into a new company called SpringWorks Therapeutics. And much like Axovant, Pfizer too is starting out with a mega-round of US$ 103 million in venture capital funding. SpringWorks is getting considerable financial support from Pfizer and funds like Bain Capital Life Sciences, Bain Capital Double Impact, Orbimed and LifeArc. Pfizer has spent US$ 24 billion over the past three years on R&D, the third highest R&D spend amongst pharma companies. Along with drug-focused acquisitions, Pfizer has spent US$ 43 billion in the same period. Ibrance to brighten up Pfizer’s fortunes: Meanwhile, Pfizer’s breast cancer drug Ibrance now competes with Novartis’ Kisqali. It will also compete with Lilly’s forthcoming drug abemaciclib. Though side effects are an issue for all the three drugs, Ibrance is expected to brighten up Pfizer’s fortunes. According to Morgan Stanley, Ibrance could bring in sales of US$ 939 million in the third quarter and US$ 1 billion in the fourth quarter, leading to US$ 3.5 billion in sales for 2017. And in 2018, Ibrance could fetch US$ 4.85 billion in sales. Novartis vows to slash drug development costs, while FDA terms system ‘broken’ The time and cost of taking a medicine from discovery to market has for long been seen as a drag on the pharmaceutical industry’s performance. The process has been estimated to take up to 14 years and cost at least US$ 2.5 billion. Last week, Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, said the clinical trials system is “broken” and there needs to be new ways to collect and utilize patient data. She was speaking at a workshop on real world evidence (RWE) at the National Academies of Sciences, Engineering, and Medicine. This week, the incoming chief executive of Novartis, Vas Narasimhan, has vowed to slash drug development costs, and save up to 25 per cent on multibillion-dollar clinical trials as part of a “productivity revolution” at the company. Quoting analysts, Narasimhan said between 10 and 25 per cent of trial costs could be reduced if digital technology were used to carry them out more efficiently. The Swiss drug major has 200 drug development projects under way and is running 500 trials. Therefore, digital technology “will have a big effect if we can do it at scale,” he added. Narasimhan plans to partner with, or acquire, artificial intelligence and data analytics companies, to supplement Novartis’s strong but “scattered” data science capability. After Pfizer, Takeda may soon exit Brazil; seeks suitors for Multilab Not long ago, Brazil was one of the hottest emerging markets for drugs, and big pharma were lining up to cash in on this opportunity. Today, Brazil is in the midst of a historic recession that has dampened drug demand. In July this year, Pfizer relinquished its 40 percent stake in the Brazilian generic drug firm — Laboratório Teuto Brasileiro — for a paltry 1 Brazilian Real (or US$ 0.30) to the heirs of the company. Pfizer had acquired the stake for US$ 240 million back in 2010. And this month, it looks like Japan's largest pharmaceutical company Takeda is following Pfizer’s footsteps and is going to dispose off its 2012 acquisition of Multilab laboratory (which it had acquired for Brazilian Real 500 million or US$ 158 million). According to news reports, Takeda may recover only a fifth of its original investment (of Brazilian Real 100 million or US$ 31.57 million). Takeda is expected to receive proposals for Multilab from mutual funds and domestic companies with similar business interests. FDA issues warning on Ocaliva (obeticholic acid) use; Allergan’s NASH drug also stumbles The US FDA issued a warning as 19 patients died after taking Intercept’s liver disease drug Ocaliva. The company responded by saying the dosing administered was incorrect. In most cases, the exact cause of death wasn’t known. But seven of the patients who died were taking Ocaliva more frequently than recommended, the FDA said. Earlier this month, Intercept had warned doctors that Ocaliva can cause injuries, organ failure, or death if it’s not used exactly as intended in patients with primary biliary cholangitis, a relatively rare liver condition for which the drug was approved last year. The company says it is working with the FDA on revised labeling aimed at more clearly indicating the recommended dosing regimen for all patients. Intercept is in the final stages of testing Ocaliva for nonalcoholic steatohepatitis, or NASH, a silent disease in which the liver gets inflamed and damaged due to a buildup of fat. Dozens of pharma companies including Gilead Sciences, Allergan and Intercept Pharmaceuticals are trying to develop a treatment for the disease. Over the last two years, at least six deals valued at US$ 3.52 billion or more have taken place involving drugs that target various aspects of NASH. Meanwhile, Allergan’s Cenicriviroc (CVC) showed mixed results in a Phase 2b clinical trial. CVC is facing trials for the treatment of liver fibrosis in adult NASH patients. The trial involved a two-year study. According to Seeking Pharma, 20 percent of patients in the placebo arm during year one who crossed over to receive CVC during year two achieved the combined endpoint of reduction in fibrosis by at least one stage and no worsening of NASH compared to 13 percent for those who continued on placebo. However, “there was no difference between CVC and placebo in patients who remained on treatment for two years as determined by the composite endpoint,” it added. Another setback for Biocon/Mylan, as Amgen files patent infringement case in US News doesn’t seem to be getting better for the Biocon/Mylan combine. First, they withdrew their applications for the trastuzumab and pegfilgrastim biosimilars from Europe. And then, the FDA extended the target action date for their trastuzumab biosimilar. Now, the duo will be facing Amgen in court to defend themselves in a patent infringement case. Last week, Amgen filed a complaint for patent infringement under the Biologics Price Competition Innovation Act (BPCIA) against Mylan, which is developing a biosimilar of its drug Neulasta (pegfilgrastim). Approval delays, spiraling compliance costs and now litigation expenses won’t help the profitability of Mylan-Biocon’s endeavors. In Europe, competition is already moving ahead as the EMA’s Committee for Medicinal Products for Human Use recommended the approval of Samsung’s Herceptin-referencing biosimilar Ontruzant. This is the fourth patent litigation under the BPCIA regarding a proposed biosimilar of Neulasta, none of which are yet FDA-approved. Amneal in merger talks with Impax Laboratories Analysts have been predicting a consolidation in the world of generics. According to reports, Impax is in merger talks with generics competitor Amneal Pharmaceuticals. The deal would value Impax at US$ 2 billion or more. According to FiercePharma, the talks could result in a deal next month. Impax is headed by Paul Bisaro (who quit Allergan to join Impax in March this year). He has considerable experience in M&As. Last year, Bisaro sold off part of Allergan’s business to Teva Pharmaceuticals in a US$ 40.5 billion deal. And last month, Shanghai Fosun Pharmaceutical picked up a 5.2 percent stake in Impax. Amneal, on the other hand, is owned by Chintu and Chirag Patel.

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28 Sep 2017

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Move over Statins, Sartans, Tinibs; it’s time for “Cholic chemistry”

Recently, FDA approved therapies to reduce double chin (yes it’s possible!) and treat patients with bile acid synthesis disorders through compounds derived from bile acids. Bile, that bitter, alkaline liquid secreted by livers, has formed the base for producing Cholic Acid and Deoxycholic Acid, which led to the recent approvals: Kythera Pharamceutical’s ATX-101 (Deoxycholic Acid, DCA) injection for submental fat (double chin) and AskLepion’s CHOLBAM (Cholic Acid, CA) capsules for the treatment of bile acid synthesis due to single enzyme defects. Kythera modified the age old French practice of mesotherapy (non-surgical cosmetic medicine treatment), where the combination of deoxycholic acid and phosphatidylcholine is used to reduce fat by demonstrating that dexoxycholic acid alone can get the job done. While the combination is used in mesotherapy, studies have demonstrated that phosphatidylcholine has a limited role in fat reduction, so Kythera’s science doesn’t exactly qualify as revolutionary. Kythera’s ability to navigate the complex regulatory landscape (they won a unanimous approval 17-0 from the FDA Advisory Committee) seems well worth it as ATX-101’s sales potential of $300 million makes Kythera a potential takeover target for larger pharmaceutical companies. The two approvals is a resurgence for bile acid salts since Cholic Acid has been used for decades to produce Ursodiol (Ursodeoxycholic Acid), a treatment for gallstones with pharma majors like Sanofi and Roche having manufactured the active ingredient in the past. There is more to come in the story of bile acid salts as they form the base for breakthrough treatments for Nonalcoholic Steatohepatitis (NASH) - a serious chronic liver disease which can lead to cirrhosis, eventual liver failure and death. There are currently no drugs approved for the treatment of NASH and recent epidemiological studies estimate that more than 10% of the U.S. adult population has NASH, with more than 60% of patients (potentially more than 14 million in total) have liver fibrosis, or cirrhosis, due to progression of the disease. Intercept Pharmaceuticals, with its modified bile acid Obeticholic Acid (OCA), has been assigned Breakthrough Therapy status by the FDA. The effectiveness of Obeticholic Acid and size of the patient population explains why Intercept has been a darling of the stock market through 2014, especially as the product is expected to gain approval later this year. Expected sales estimates of the potential blockbuster range between $2-4 billion and explain the $6 billion stock market valuation. Further upstream, Israel based, Galmed Pharmaceuticals has a compound in Phase IIb clinical trials which couples Cholic Acid with the commonly available fatty acid, Arachidic Acid for the same indication as Obeticholic Acid. After Gilead’s recent purchase of Phenex Pharmaceuticals for $470 million to get access to their NASH compound, the potential upside of NASH compounds is HUGE! We already have established molecule classes like Statins, Sartans & Tinibs, maybe it’s time to get work started on "Cholic chemistry”! Search our database for Cholic Acid and Deoxycholic Acid to find suppliers, pricing information and a lot more…

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26 Mar 2015

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Find PharmaFlow Article for 0462Z4S4OZ

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Synopsis

Chemistry

APIs // Active Pharmaceutical Ingredients

29 API Suppliers

11 USDMF

6 EU WC

11 NDC API

25 Listed Suppliers

DEVELOPMENTS

31 Drug(s) in Development

PRICE INFORMATION

API Reference Price

API Exports

API Imports

FDF Imports

INTERMEDIATES

17 Suppliers

DOSSIERs // Finished Dosage Formulations

21 Dossiers

9 FDA Orange Book

2 Europe

2 Canada

5 Australia

3 Listed Dossiers

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3 Prachin Chemical

3 Anhui Sunhere Pharmaceutical Excipients Co.,Ltd

3 DFE Pharma

3 Ideal Cures Pvt Ltd

3 Vasa Pharmachem

2 Pharmatrans-Sanaq

2 Shanghai Shenmei Pharmaceutical Technology Co., Ltd

1 Nanjing Well Pharmaceutical

1 BASF

1 Ingredion Pharma Solutions

1 SPI Pharma

1 DKSH

1 Aeon Procare

EXCIPIENTS BY APPLICATIONS

21 Fillers, Diluents & Binders

17 Coating Systems & Additives

17 Disintegrants & Superdisintegrants

14 Lubricants & Glidants

12 Direct Compression

10 Thickeners and Stabilizers

9 Controlled & Modified Release

6 Granulation

6 Co-Processed Excipients

5 Film Formers & Plasticizers

3 Taste Masking

2 Parenteral

2 Topical

2 Chewable & Orodispersible Aids

1 API Stability Enhancers

1 Rheology Modifiers

1 Emulsifying Agents

GLOBAL SALES INFORMATION

7 US Medicaid Prescriptions

2 Finished Drug Prices

MARKET PLACE

10 APIs

3 DOSSIERS // FDF

PATENTS

14 US Patents

DIGITAL CONTENT

3 Data Compilations & Company Tracker #PharmaFlow

63 News

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