Tetrabenazine
Top drugs and pharmaceutical companies of 2019 by revenues
Acquisitions and spin-offs dominated headlines in 2019 and the tone was set very early with Bristol-Myers Squibb acquiring New Jersey-based cancer drug company Celgene in a US$ 74 billion deal announced on January 3, 2019. After factoring in debt, the deal value ballooned to about US$ 95 billion, which according to data compiled by Refinitiv, made it the largest healthcare deal on record. In the summer, AbbVie Inc, which sells the world’s best-selling drug Humira, announced its acquisition of Allergan Plc, known for Botox and other cosmetic treatments, for US$ 63 billion. While the companies are still awaiting regulatory approval for their deal, with US$ 49 billion in combined 2019 revenues, the merged entity would rank amongst the biggest in the industry. View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available) The big five by pharmaceutical sales — Pfizer, Roche, J&J, Novartis and Merck Pfizer continued to lead companies by pharmaceutical sales by reporting annual 2019 revenues of US$ 51.8 billion, a decrease of US$ 1.9 billion, or 4 percent, compared to 2018. The decline was primarily attributed to the loss of exclusivity of Lyrica in 2019, which witnessed its sales drop from US$ 5 billion in 2018 to US$ 3.3 billion in 2019. In 2018, Pfizer’s then incoming CEO Albert Bourla had mentioned that the company did not see the need for any large-scale M&A activity as Pfizer had “the best pipeline” in its history, which needed the company to focus on deploying its capital to keep its pipeline flowing and execute on its drug launches. Bourla stayed true to his word and barring the acquisition of Array Biopharma for US$ 11.4 billion and a spin-off to merge Upjohn, Pfizer’s off-patent branded and generic established medicines business with Mylan, there weren’t any other big ticket deals which were announced. The Upjohn-Mylan merged entity will be called Viatris and is expected to have 2020 revenues between US$ 19 and US$ 20 billion and could outpace Teva to become the largest generic company in the world, in term of revenues.  Novartis, which had followed Pfizer with the second largest revenues in the pharmaceutical industry in 2018, reported its first full year earnings after spinning off its Alcon eye care devices business division that had US$ 7.15 billion in 2018 sales. In 2019, Novartis slipped two spots in the ranking after reporting total sales of US$ 47.4 billion and its CEO Vas Narasimhan continued his deal-making spree by buying New Jersey-headquartered The Medicines Company (MedCo) for US$ 9.7 billion to acquire a late-stage cholesterol-lowering therapy named inclisiran. As Takeda Pharmaceutical Co was busy in 2019 on working to reduce its debt burden incurred due to its US$ 62 billion purchase of Shire Plc, which was announced in 2018, Novartis also purchased the eye-disease medicine, Xiidra, from the Japanese drugmaker for US$ 5.3 billion. Novartis’ management also spent a considerable part of 2019 dealing with data-integrity concerns which emerged from its 2018 buyout of AveXis, the gene-therapy maker Novartis had acquired for US$ 8.7 billion. The deal gave Novartis rights to Zolgensma, a novel treatment intended for children less than two years of age with the most severe form of spinal muscular atrophy (SMA). Priced at US$ 2.1 million, Zolgensma is currently the world’s most expensive drug. However, in a shocking announcement, a month after approving the drug, the US Food and Drug Administration (FDA) issued a press release on data accuracy issues as the agency was informed by AveXis that its personnel had manipulated data which the FDA used to evaluate product comparability and nonclinical (animal) pharmacology as part of the biologics license application (BLA), which was submitted and reviewed by the FDA. With US$ 50.0 billion (CHF 48.5 billion) in annual pharmaceutical sales, Swiss drugmaker Roche came in at number two position in 2019 as its sales grew 11 percent driven by its multiple sclerosis medicine Ocrevus, haemophilia drug Hemlibra and cancer medicines Tecentriq and Perjeta. Roche’s newly introduced medicines generated US$ 5.53 billion (CHF 5.4 billion) in growth, helping offset the impact of the competition from biosimilars for its three best-selling drugs MabThera/Rituxan, Herceptin and Avastin. In late 2019, after months of increased antitrust scrutiny, Roche completed its US$ 5.1 billion acquisition of Spark Therapeutics to strengthen its presence in gene therapy. Last year, J&J reported almost flat worldwide sales of US$ 82.1 billion. J&J’s pharmaceutical division generated US$ 42.20 billion and its medical devices and consumer health divisions brought in US$ 25.96 billion and US$ 13.89 billion respectively.  Since J&J’s consumer health division sells analgesics, digestive health along with beauty and oral care products, the US$ 5.43 billion in consumer health sales from over-the-counter drugs and women’s health products was only used in our assessment of J&J’s total pharmaceutical revenues. With combined pharmaceutical sales of US$ 47.63 billion, J&J made it to number three on our list. While the sales of products like Stelara, Darzalex, Imbruvica, Invega Sustenna drove J&J’s pharmaceutical business to grow by 4 percent over 2018, the firm had to contend with generic competition against key revenue contributors Remicade and Zytiga. US-headquartered Merck, which is known as MSD (short for Merck Sharp & Dohme) outside the United States and Canada, is set to significantly move up the rankings next year fueled by its cancer drug Keytruda, which witnessed a 55 percent increase in sales to US$ 11.1 billion. Merck reported total revenues of US$ 41.75 billion and also announced it will spin off its women’s health drugs, biosimilar drugs and older products to create a new pharmaceutical company with US$ 6.5 billion in annual revenues. The firm had anticipated 2020 sales between US$ 48.8 billion and US$  50.3 billion however this week it announced that the coronavirus  pandemic will reduce 2020 sales by more than $2 billion. View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available)  Humira holds on to remain world’s best-selling drug AbbVie’s acquisition of Allergan comes as the firm faces the expiration of patent protection for Humira, which brought in a staggering US$ 19.2 billion in sales last year for the company. AbbVie has failed to successfully acquire or develop a major new product to replace the sales generated by its flagship drug. In 2019, Humira’s US revenues increased 8.6 percent to US$ 14.86 billion while internationally, due to biosimilar competition, the sales dropped 31.1 percent to US$ 4.30 billion. Bristol Myers Squibb’s Eliquis, which is also marketed by Pfizer, maintained its number two position and posted total sales of US$ 12.1 billion, a 23 percent increase over 2018. While Bristol Myers Squibb’s immunotherapy treatment Opdivo, sold in partnership with Ono in Japan, saw sales increase from US$ 7.57 billion to US$ 8.0 billion, the growth paled in comparison to the US$ 3.9 billion revenue increase of Opdivo’s key immunotherapy competitor Merck’s Keytruda. Keytruda took the number three spot in drug sales that previously belonged to Celgene’s Revlimid, which witnessed a sales decline from US$ 9.69 billion to US$ 9.4 billion. Cancer treatment Imbruvica, which is marketed by J&J and AbbVie, witnessed a 30 percent increase in sales. With US$ 8.1 billion in 2019 revenues, it took the number five position. View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available) Vaccines – Covid-19 turns competitors into partners This year has been dominated by the single biggest health emergency in years — the novel coronavirus (Covid-19) pandemic. As drugs continue to fail to meet expectations, vaccine development has received a lot of attention.  GSK reported the highest vaccine sales of all drugmakers with total sales of US$ 8.4 billion (GBP 7.16 billion), a significant portion of its total sales of US$ 41.8 billion (GBP 33.754 billion).   US-based Merck’s vaccine division also reported a significant increase in sales to US$ 8.0 billion and in 2019 received FDA and EU approval to market its Ebola vaccine Ervebo. This is the first FDA-authorized vaccine against the deadly virus which causes hemorrhagic fever and spreads from person to person through direct contact with body fluids. Pfizer and Sanofi also reported an increase in their vaccine sales to US$ 6.4 billion and US$ 6.2 billion respectively and the Covid-19 pandemic has recently pushed drugmakers to move faster than ever before and has also converted competitors into partners. In a rare move, drug behemoths  — Sanofi and GlaxoSmithKline (GSK) —joined hands to develop a vaccine for the novel coronavirus. The two companies plan to start human trials in the second half of this year, and if things go right, they will file for potential approvals by the second half of 2021.  View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available)  Our view Covid-19 has brought the world economy to a grinding halt and shifted the global attention to the pharmaceutical industry’s capability to deliver solutions to address this pandemic.  Our compilation shows that vaccines and drugs for infectious diseases currently form a tiny fraction of the total sales of pharmaceutical companies and few drugs against infectious diseases rank high on the sales list. This could well explain the limited range of options currently available to fight Covid-19. With the pandemic currently infecting over 3 million people spread across more than 200 countries, we can safely conclude that the scenario in 2020 will change substantially. And so should our compilation of top drugs for the year. View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available)   

Impressions: 54754

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#PharmaFlow by PHARMACOMPASS
29 Apr 2020
Ghosts of GSK’s billion dollar mistake return; New date for electronic submissions of DMFs
This week, Phispers tells us why David Hung’s taking charge as CEO of Axovant could signal the revival of an Alzheimer’s compound shelved by GSK. While, the FDA has extended compliance date for submitting DMFs in electronic format, there are also indications that there will be more FDA inspections in India. Plus, there is news on companies like Fresenius, Stada, Ajanta Pharma, Merck and Teva. Read on.   FDA extends compliance date for electronic DMF submissions to May, 2018   On April 7, the US Food and Drug Administration (FDA) announced it is extending the compliance date  for submitting DMFs in Electronic Common Technical Document (eCTD) format to May 5, 2018. “DMF submissions that are not submitted in eCTD format after this date will be rejected,” the FDA website said. “Presentations on submitting in eCTD format created prior to April 7, 2017 will have the incorrect compliance date for DMFs,” it added. Electronic submissions of Drug Master Files (DMFs) were supposed to become mandatory from May 5, 2017.  The news coincides with the US Senate’s confirmation hearing for Scott Gottlieb, on April 7. Gottlieb was President Trump’s nominee to be the next Commissioner of the FDA. Gottlieb was with the FDA when the regulator launched its Pharmaceutical cGMPs for the 21st Century initiative. Out of five guidance documents listed as part of this initiative, only one has been finalized. With Gottlieb heading back, Ajaz Hussain, (former FDA deputy office director and president of the National Institute for Pharmaceutical Technology and Education of NIPTE), Vadim Gurvich (executive director of NIPTE) and Peter J. Pitts (president of the Center for Medicine in the Public Interest and a former FDA associate commissioner) shared their perspective on how Trump and the FDA can create a pharmaceutical manufacturing renaissance in a blog posted on Morning Consult. Axovant appoints new CEO and revives ghosts of GSK’s billion dollar mistake   After selling Medivation to Pfizer for US $ 14 billion and exiting with US $ 354 million for himself, David Hung is now the CEO of Axovant, the company which we wrote about two years ago, as we asked the question — Did a 29-year old show GSK that it made a billion dollar mistake? Back in December 2014,Vivek Ramaswamy, CEO and Founder of Roivant Neurosciences and Axovant, had bought an old Alzheimer’s drug that GSK had dropped for US $ 5 million. In October 2014, Roivant had spun off a subsidiary by the name of Axovant, which then bought the GSK drug. GSK had shelved the compound — 5HT6 — after testing it in 13 trials and on 1,250 patients. Six months after purchasing the compound from GSK, and without doing any clinical development, the drug resulted in the biggest biotech IPO ever for Axovant, which got valued at US $ 2 billion. Since then, Ramaswamy has been setting up more companies. Throughout, Ramaswamy has recruited high-profile executives to run his companies. And who could be more high profile than Hung? The stock market cheered his appointment — Axovant’s stock was up 28 percent earlier this week after Hung was announced its CEO. Axovant is looking for positive data that GSK had gathered for its 5HT6 Alzheimer’s drug. And a number of senior players in the industry say Axovant has a decent shot at taking the successful dose back into the clinic. With Hung joining, it seems the drug discarded by GSK does indeed have merit. Fresenius in talks to buy Akorn; Stada sold for US $5.6 billion   Fresenius SE said it is in talks to buy US generic drugmaker - Akorn Inc. Though discussions are underway, there is no certainty of a deal, Fresenius said. A spokeswoman for Akorn declined to comment. The CEO of Fresenius, Stephan Sturm, who took charge in July 2016, has been expanding the group’s global reach through acquisitions. Last year, the company bought Spanish hospital group IDC Salud Holding SLU, also known as Quironsalud, for US $ 6.11 billion (Euro 5.76 billion) in the company’s largest-ever acquisition. Akorn could complement Fresenius’ Kabi medicines division, which specializes in intravenous drugs, and accounts for about a fifth of the company’s revenue. Stada sell-off: Stada Arzneimittel AG has been sold to Bain Capital and Cinven for US $ 5.6 billion (Euros 5.3 billion), after a long-fought takeover contest. The sell-off will give the equity firms control of one of the last independent generic-drug businesses in Europe. The deal would give buyers access to German and Russian markets for OTC and copycat medicines. It marks another step in the consolidation of the generics industry.  FDA inspections in India to rise, says Edelweiss Securities   India’s pharmaceutical sector is the largest supplier of drugs to the US. However, “quality issues are an ongoing challenge for the Indian pharmaceutical industry,” Mary Lou Valdez, FDA’s associate commissioner for international programs wrote in a blog.  Of the 42 warning letters sent out by FDA’s office of manufacturing quality last year, about one-fifth (9) were addressed to Indian facilities. The number could rise over the next three years as the FDA would inspect 190 facilities that it could not inspect in the past five years, wrote Edelweiss Securities.  FDA inspections in India and China have doubled since 2012. This has led to a spurt in warning letters as well. GSK to withdraw 600,000 inhalers; no observations for Ajanta   GSK would be voluntarily recalling close to 600,000 Ventolin asthma inhalers across the US, says the FDA. The recall is due to a leak observed in some of the products. The exact number of inhalers to be recalled, as reported by the FDA, is 593,088. These were produced in GSK’s Zebulon, North Carolina manufacturing facility. This is the second time in just over a year that the plant has faced problems with leaking inhalers. Ajanta Pharma: On Monday this week, shares of India-based Ajanta Pharma soared by over 5 percent in intraday trading as investors cheered the fact that no observations were issued during a regulatory inspection at its unit. “Our formulation facility at Dahej (in Gujarat) was inspected by US Food and Drug Administration (FDA) from April 3 to April 7, 2017. At the end of the inspection, no Form 483 was issued to us,” Ajanta Pharma said in a notification to the stock exchanges. FDA delivers a blow to Merck’s Januvia marketing plan    In 2015, Merck had come out with a massive 14,724-patient study where the data demonstrated that Type 2 diabetes patients could take its flagship DPP-4 drug — Januvia — without increasing their risk for cardio complications. DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.  Merck wanted to use the findings of this survey in a label to help distinguish themselves from same-class rivals like Onglyza, which has risks. However, the FDA recently nixed the idea, handing the pharma giant a complete response letter (CRL). The CRL covered Merck’s blockbuster Januvia as well as its combos with metformin. However, Merck says it is reviewing the letter and will discuss next steps with the FDA. Teva’s US $ 3.5 billion buy pays off with FDA approval of Austedo   Last week, the FDA gave its nod for Teva’s promising drug deutetrabenazine, after putting it on hold ten months back due to certain suspicions regarding some metabolites found in patients. Teva had paid US $ 3.5 billion to acquire Auspex two years back. Teva’s deutetrabenazine is the first deuterated drug to bag an FDA approval. A deuterated drug is a drug where hydrogen has been replaced by deuterium. A simple swap of six hydrogens with deuterium in an existing drug, Xenazine® (tetrabenzaine), resulted in an improved version of the drug, called deutetrabenzaine or SD-809 (which had been developed by Auspex). The drug will be sold as Austedo. Due to the presence of deuterium, the drug breaks down more slowly in patients. This way physicians can give the drug less often and at lower doses and still manage great results. The drug is designed to regulate the levels of dopamine in the brain.  

Impressions: 3020

https://www.pharmacompass.com/radio-compass-blog/ghosts-of-gsk-s-billion-dollar-mistake-return-new-date-for-electronic-submissions-of-dmfs

#PharmaFlow by PHARMACOMPASS
13 Apr 2017
Teva and Otsuka’s Multi-Billion dollar plan when blockbusters turn Generic: Deuterium Chemistry
Two blockbusters, Otsuka’s Abilify® (aripiprazole) and Teva’s Copaxone® (glatiramer acetate), with combined sales of more than $10 billion in 2014 are going to face severe generic competition this year. Interestingly, both companies have turned to a new technology platform, which uses deuterium chemistry analogs of old, off-patent drugs to secure their future profits.  A simple swap of six hydrogens with deuterium in an existing drug, Xenazine® (tetrabenzaine), resulted in an improved version of the drug, called deutetrabenzaine or SD-809. This improved version breaks down more slowly in the body, allowing physicians to give it less often and at lower doses. The worth was established, when Teva paid $3.5 billion for the company Auspex, which developed SD-809.   SD-809 is expected to be approved in 2016 for the potential treatment of chorea (abnormal involuntary writhing movements), associated with central nervous system disorders like Huntington’s disease, tardive dyskinesia, and Tourette syndrome. Now, while this may have sounded like complex chemistry, you’ll be surprised by the simplicity of the concept.   What is this deuterium that replaced the hydrogen? Deuterium is a non-radioactive, stable and naturally occurring hydrogen isotope. The atomic mass of hydrogen is approximately 1.0 atomic mass unit (AMU), while that of deuterium is approximately 2.0 AMU. We all have 1-2g of deuterium in our bodies.   Why does a deuterium swap make a difference? Replacing some hydrogen atoms with deuterium does not change the shape or electronic structure of the molecule, but it can make a big difference in how it behaves. The reason: chemical bonds formed with deuterium are generally stronger and longer-lasting than those with hydrogen. Stronger bonds allow for small molecule drugs to resist to metabolic enzymes in the body that break down weaker hydrogen bonds. The result: the drug is broken down slower in the body, stays longer and hence is not required in high doses or as often. In addition, the deuterated drug is more stable in the presence of other drugs, resulting in reduced drug-drug interactions.   What did Teva & Otsuka buy? Teva: In addition to Auspex’s lead compound, SD-809, Teva also procured other pipeline candidates, which include deuterated versions of levodopa for Parkinson’s disease and pirfenidone for idiopathic pulmonary fibrosis.  As Roche purchased InterMune® $8.3 billion last year needs to get changed to “As Roche purchase Intermune for $8.3 billion last year” Otsuka’s $3.5 billion acquisition of Avanir Pharmaceuticals involved a pipeline of products, which are combinations of common, cough syrup ingredient, dextromethorphan with an old-heart drug, quinidine.    The promise of deuterated dextromethorphan for Alzheimer’s disease (Avanir compound AVR-786) was a key driver for Otsuka to purchase Avanir. The challenges and opportunities It can be difficult and not always clear to figure out where exactly to swap the deuterium for maximum effect. Legally, a deuterated compound is only considered a new drug if there is sufficient difference in the “active moiety” structure because initially the FDA had considered tetrabenzaine and deutetrabenzaine (SD-809) to be the same drug!  However, deuterium chemistry, while simple, requires specialization, which serves as an opportunity for chemical companies to consider developing.  With almost $7 billion in acquisitions in under 6 months, deuterium chemistry does deserve attention.  

Impressions: 4754

https://www.pharmacompass.com/radio-compass-blog/teva-and-otsuka-s-multi-billion-dollar-plan-when-blockbusters-turn-generic-deuterium-chemistry

#PharmaFlow by PHARMACOMPASS
21 May 2015
The Next Generic Attack: Brilinta® (Ticagrelor), Xarelto® (Rivaroxaban), Tradjenta® (Linagliptin) and…
With almost 30,000 Drug Master Files (DMFs) submitted to the FDA, reviewing the filings of only the first quarter of 2015, provides an indicator on the current areas of focus of generic pharmaceutical companies. A detailed evaluation of the 241 filings for active pharmaceutical ingredients only, made us find some interesting trends worth sharing. European Blockbuster battle! Of the 241 DMFs, 21 APIs had more than one DMF filing and accounted for 25% of the total filings. Interestingly, 20 DMFs  were for only three APIs: AstraZeneca’s blood thinner Brilinta® (Ticagrelor), with 2014 sales of $476 million, already had DMF filings from Dr. Reddy’s, Mylan, Polpharma and Zhejiang Hisun at the end of last year. With a maximum of 9 new filings from players like Teva, Alembic, Lek and others, AstraZeneca should brace itself for some serious generic onslaught.  While the 9 filings for Ticagrelor were the most for any single compound, not far behind is Bayer’s own blood thinner: Xarelto® (Rivaroxaban). With 7 submissions, the focus of the generic companies is understandable as Rivaroxaban had sales in excess of $3 billion and year-on-year growth in excess of 70%. However, patents currently protect the product till 2020, so patience is needed before generics can access this golden opportunity. Interestingly, 4 filings for Linagliptin (Boehringer’s antidiabetic Tradjenta®) make it yet another European pharma giant lead the list of products being subjected to generic competition, and make us wonder why European blockbusters are preferred over others? Exclusive but not patented There are products, which have no patent protection, but the market is protected by FDA granted exclusivities (learn more on patents and exclusivities from the FDA website). An opportunity for generic companies to gain significant market share of a multi-hundred million dollar market, without any litigation risk or cost is something companies dream about.  As the time of exclusivity expiry nears, Clobazam, Tetrabenazine, Hydroxyprogesterone Caproate, Deferiprone and Trypan Blue will all see increased generic activity as their Drug Master Files have been submitted. Fragmented Activity More than 80% of the DMF submissions were made by companies who filed only a single product. While the products varied from simple compounds like Sodium Chloride to biologics like Plasmid DNA, over 140 companies filed DMFs in the first quarter with almost 30 submitting a DMF for the first time. An expanding list of suppliers who support DMFs increases options for sourcing managers.  However, a fragmented supplier base limits the industrial scale companies can achieve and raises concerns regarding how many can successfully sustain compliance standards under increased regulatory scrutiny? The Next Generic Wave Blood thinners are an opportunity few generic companies wish to pass on. Boehringer’s (Dabigatran Etexilate), Bristol-Myers Squibb’s (Apixaban) and Bayer’s (Rivaroxaban) are novel compounds in this category which had combined sales in excess of $5 billion last year.  While Dagibatran saw a flurry of activity over the last two years with almost 15 DMF filings, there were no additional filings this year. On the other hand, Apixaban, which generated $774 million for Bristol-Myers Squibb in 2014, has only one DMF filing at the moment and that too was done over a year ago. The export data out of India, reviewed on PharmaCompass, for Apixaban, indicates that product development is already complete so it is just a matter of time before the filings begin.   Conclusion: Product and supplier selection is a critical component of every generic company’s strategy. The PharmaCompass database is designed to assist professionals in business development, marketing and sourcing to take more informed decisions. If you would like us to share our shortlist of 241 DMFs, we will be happy to send it to you by email (click here). You can also access our compilation of the 2014 annual reports of major pharmaceutical companies to review the various products along with their revenues (click here): Table: Products with more than one DMF filing in Q1 2015 PRODUCT NAME DMF FILINGS TICAGRELOR 9 RIVAROXABAN 7 LINAGLIPTIN 4 APREPITANT 3 CINACALCET HYDROCHLORIDE 3 ATAZANAVIR SULFATE 2 ATORVASTATIN CALCIUM TRIHYDRATE 2 CLOBAZAM 2 CLOFARABINE 2 DEFERASIROX 2 DIMETHYL FUMARATE 2 EZETIMIBE 2 ICATIBANT ACETATE 2 LURASIDONE HYDROCHLORIDE 2 MELPHALAN HYDROCHLORIDE 2 OLANZAPINE 2 OLMESARTAN MEDOXOMIL USP 2 PRASUGREL HYDROCHLORIDE 2 RIVASTIGMINE USP 2 ROSUVASTATIN CALCIUM 2 SOLIFENACINE SUCCINATE 2

Impressions: 8782

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#PharmaFlow by PHARMACOMPASS
13 May 2015