The market share in sales for top chains keeps increasing, as their sales grow faster than industry average.
Source: 中国药店，中信证券
* the total drug retail sales data is a little different from the previous post China Medicine End Market Sales (2018: 391.9 vs. 400.2 billion RMB, 2% higher in this report)
As a treatment: Prescription opioids can be used to treat moderate-to-severe pain and are often prescribed following surgery or injury, or for health conditions such as cancer.
In recent years, there has been a dramatic increase in the acceptance and use of prescription opioids for the treatment of chronic, non-cancer pain, such as back pain or osteoarthritis, despite serious risks and the lack of evidence about their long-term effectiveness.
Source: IQVIA
Prescription opioid usage in the United States increased considerably from the mid 1990’s to its peak in 2011, at 240 billion MMEs (morphine milligram equivalents). It is now declining rapidly with the largest single year change in 2017 with a decline of 23.3 billion MMEs or 12.0%.
The most common drugs involved in prescription opioid overdose deaths include:
Methadone
Oxycodone (such as OxyContin®)
Hydrocodone (such as Vicodin®)
Abuse Deterrent
What is an Abuse Deterrent Opioid: with abuse-deterrent formulation properties that are expected to meaningfully deter certain types of abuse and/or make abuse more difficult or less rewarding.
Physical/chemical barriers – Physical barriers can prevent chewing, crushing, cutting, grating, or grinding of the dosage form. Chemical barriers, such as gelling agents, can resist extraction of the opioid using common solvents like water, simulated biological media, alcohol, or other organic solvents. Physical and chemical barriers can limit drug release following mechanical manipulation, or change the physical form of a drug, rendering it less amenable to abuse.
Agonist/antagonist combinations – An opioid antagonist can be added to interfere with, reduce, or defeat the euphoria associated with abuse. The antagonist can be sequestered and released only upon manipulation of the product. For example, a drug product can be formulated such that the substance that acts as an antagonist is not clinically active when the product is swallowed, but becomes active if the product is crushed and injected or snorted.
Aversion – Substances can be added to the product to produce an unpleasant effect if the dosage form is manipulated or is used at a higher dosage than directed. For example, the formulation can include a substance irritating to the nasal mucosa if ground and snorted.
Delivery System (including use of depot injectable formulations and implants) – Certain drug release designs or the method of drug delivery can offer resistance to abuse. For example, sustained-release depot injectable formulation or a subcutaneous implant may be difficult to manipulate.
New molecular entities and prodrugs– The properties of a new molecular entity (NME) or prodrug could include the need for enzymatic activation, different receptor binding profiles, slower penetration into the central nervous system, or other novel effects. Prodrugs with abuse-deterrent properties could provide a chemical barrier to the in vitro conversion to the parent opioid, which may deter the abuse of the parent opioid. New molecular entities and prodrugs are subject to evaluation of abuse potential for purposes of the Controlled Substances Act (CSA).
Combination – Two or more of the above methods could be combined to deter abuse.
Novel approaches – This category encompasses novel approaches or technologies that are not captured in the previous categories.
Opioids with FDA-Approved Labeling Describing Abuse-Deterrent Properties
Opioids are drugs formulated to replicate the pain-educing properties of opium. Prescription painkillers like morphine (吗啡), oxycodone (羟考酮) and hydrocodone (氢可酮) are opioids.
There are four categories:
Natural opioids (including morphine and codeine 可待因) and semi-synthetic opioids (drugs like oxycodone, hydrocodone, hydromorphone 氢吗啡酮, and oxymorphone 羟吗啡酮)
Methadone (美沙酮), a synthetic opioid
Synthetic opioids other than methadone (drugs like tramadol and fentanyl)
Heroin, an illicit (illegally made) opioid synthesized from morphine that can be a white or brown powder, or a black sticky substance.
Hydrocodone (such as Vicodin) and oxycodone (such as OxyContin) are semi-synthetic opioids, manufactured in labs with natural and synthetic ingredients.
Fentanyl is a fully synthetic opioid, originally developed as a powerful anesthetic for surgery. It is also administered to alleviate severe pain associated with terminal illnesses like cancer. The drug is up to 100 times more powerful than morphine.
Methadone is another fully synthetic opioid. It is commonly dispensed to recovering heroin addicts to relieve the symptoms of withdrawal.
Three Waves of Opioid Overdose Deaths
From 1999-2017, almost 400,000 people died from an overdose involving any opioid, including prescription and illicit opioids.
The first wave began with increased prescribing of opioids in the 1990s 3, with overdose deaths involving prescription opioids (natural and semi-synthetic opioids and methadone) increasing since at least 1999.
The second wave began in 2010, with rapid increases in overdose deaths involving heroin.
The third wave began in 2013, with significant increases in overdose deaths involving synthetic opioids – particularly those involving illicitly-manufactured fentanyl (IMF). The IMF market continues to change, and IMF can be found in combination with heroin, counterfeit pills, and cocaine.
The lack of talents has been a well-recognized problem for China’s biotech industry[1]. China lacks seasoned experts with at least 10 years’ industry experience, say insiders. Companies are especially keen on experience in translational medicine, early-stage clinical trials and antibody manufacturing. Start-up biotech firms need experienced managers at every level, from clinical trials to drug manufacturing processes, to help build their companies[2].
This path from multinational drug company to biotech is clearly seen in the bios of many of the more ambitious start-up founders. Returnees with a few years under their belt in China and an ability to effectively navigate the system are far more valuable to employers than new arrivals. It becomes fairly common that multinational biopharma firms are finding themselves battling Chinese biotechnology startups to attract talent38,[3]. Those startups flush with cash from venture-capital financing are willing to pay top dollar (and upsides with options).
Trials
In terms of conducting trials, a historical lack of clinical research infrastructure in China has led to problems adhering to Good Clinical Practice, the international gold standard for maintaining ethical and quality standards in clinical trials. As an example, nearly all clinical research sites in China are hospitals, as there are no private practices. Because of that, clinical trial participants are treated exactly the same way as regular patients. That’s a problem because study staff — who are regular hospital employees — don’t have experience complying with Good Clinical Practice, putting the trial’s integrity, not to mention patient protection, at risk[4],[5].
Meanwhile, the rapid growth of Wuxi AppTex (and its affiliated Wuxi Biologics) has made itself one of the largest CRO/CMO players in the world[6], helping to facilitate drug discovery/development/manufacturing globally.
Launches
As most Chinese biotech startups are still in the r&d stage, only a few were approved recently. The most relevant example here might be the PD-1/PD-L1 space.
CFDA has long been seen as “slow” in terms of new drug approvals. A 2016 discussion quoted that usually a new drug needs 5-10 years for approval[7].
However, for the recent domestic PD-1 drugs for cancer, the approval speed was amazingly fast. Junshi won the first made-in-China PD-1 drug approval by NMPA (formerly CFDA) in December 2018[8]. Ten days later, the second PD-1 drug by Innovent was approved[9]. Each took 284 and 255 days respectively[10].
Two foreign PD-1 drugs, Merck’s Keytruda and Bristol-Myers Squibb’s Opdivo, were approved earlier in 2018. During 18Q3, Keytrude and Opdivo recorded ¥150 and ¥190 million in sales respectively[11].
Junshi started its sales in February 2019 and recorded nearly ¥80 million in the first quarter[12]. Innovent’s PD-1 launched its sales in March 2019 and finished the first quarter with $9.9 million in revenue, both of which are deemed as successful in media reports[13].
According to IMS, China’s spending in medicine has been growing fast, reaching $137 billion in 2018[1].
Another research database shows that in 2018, China’ exports in medicine was $17.4 billion[2] and imports was $29.6 billion[3].
Although they might use different sources/measures, we could roughly estimate that in 2018, non-import medicine consumption was 137-29.6 = 107.4 billion and domestic medicine production was 107.4+17.4 = 124.8 billion.
Therefore, 86% of Chinese drug companies’ production was for the domestic market while 14% was for exports in 2018.
For the more modern (or newly funded) innovative biotech/drug companies in China, they are targeting the global markets. Usually they will divide the commercial rights by regions and retain the greater china rights while sell the rest (another source of funding). Some innovative drug candidates’ global rights ex china have already been licensed/acquired by western/US pharmaceutical companies. Most Chinese biotech companies don’t have the capability to develop/commercialize outside the greater china area.
In 2015 first quarterly report, Teva said Copaxone® 40 mg/mL accounted for 66% of total Copaxone® prescriptions in the U.S. And the US sales decline compared with 2014 Q1 mainly reflects unusually strong sales in the first quarter of 2014 due to inventory stocking in connection with the launch of Copaxone® 40 mg/mL in January 2014.
Shares in the Israeli company (Teva) were down 13% this morning – many were not expecting the FDA verdict until next year. Umer Raffat at Evercore ISI attempted to quantify the damage: earlier than expected loss of revenues could result in an annualised $480m to $640m being shaved from consensus operating profit estimates, he believes. [EvaluatePharma]
It’s a major lift for Mylan, whose anticipated 20-mg knockoff of the multiple sclerosis star has been conspicuously missing for years. A team of Novartis’ Sandoz and Momenta zoomed ahead with an April 2015 approval of their own version, Glatopa, which last year helped Sandoz’s biopharmaceuticals unit grow 25% to $772 million in sales. [FiercePharma]
According to the FDA approval letter, Mylan was one of the first applicants to submit a substantially complete ANDA for Glatiramer Acetate Injection, 40 mg/mL, containing a Paragraph IV certification. Therefore, Mylan and other first filers may be eligible for 180 days of generic drug exclusivity but FDA has not made a formal determination on exclusivity at this time.
Notably, the approval for Mylan comes a day after the FDA commissioner, Scott Gottlieb, released draft guidance to help speed the approval of complex generics like Copaxone. If any were needed, this earlier than expected green light provides further evidence that the US regulator is determined in its efforts to smooth the path to market for a wider range of copycat medicines.
Copaxone reached its global peak sales of $4.3 billion in 2013
In 2013 Teva, with total revenue over $20 billion, had a generic drug business close to $10 billion and specialty drug sales of $8.4 billion (Copaxone accounted for more than half of the specialty drug business)
Profitability 1/2
…while made 50.8% of Teva’s total profitability in 2013
Copaxone contributed a segment profitability (gross margin – S&M – R&D) of $3.3 billion, with a very healthy margin of 76%
Other specialty drugs and generic business had a margin of 32% and 17% respectively
Teva’s total profitability (gross margin – S&M – R&D) was $6.4 billion in 2013
Two “bad” (for Teva) developments in 2013
Biogen’s Tecfidera approved by FDA, which would become the leading MS drug in 2017
The United States Food and Drug Administration (FDA) announced on March 27, 2013 that it has approved Tecfidera™(dimethyl fumarate or DMF, formerly known as BG-12) as a first-line therapy for the long-term treatment of relapsing forms of multiple sclerosis (MS).
Tecfidera is administered in pill form orally (by mouth) and is the third oral DMT approved for MS. The approved dosage is 240 mg to be taken two-times daily.
The appellate court struck down some of Teva’s composition patents that were protected until that date, with the effect of allowing a launch as early as May 24, 2014
Copaxone is one of the leading drugs for multiple sclerosis (MS).
What is MS?
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system affecting more than 2 million individuals globally and approximately 400 000 in the United States. [paper]
MS 通常分为四类，其中复发缓解型多发性硬化症 relapsing-remitting MS (RRMS) 占比约 85%。[药事纵横]
Relapsing forms of MS include clinically isolated syndrome (CIS; a first demyelinating episode), relapsing-remitting MS (RRMS), secondary-progressive MS, and progressive-relapsing MS. The symptoms of MS can be highly variable, both in severity and duration, but may include visual disturbances, bladder/bowel dysfunction, weakness, impaired balance, vertigo, numbness, tingling, pain, and cognitive dysfunction. [paper]
Source: Multiple Sclerosis Association of America
Among the available drugs for MS, Copaxone has been the best-selling drug for years until 2017. In 2017 H1, Copaxone sales = $2.296 billion while Tecfidera by Biogen had a total revenue of $2.069 billion. [药事纵横]
The past decade has seen a dramatic change in the US MS-treatment landscape. While no cure for MS is currently available, treatment options exist to reduce the frequency of relapses, manage symptoms, and slow disease progression. Many US Food and Drug Administration (FDA)–approved disease-modifying therapies (DMTs) are currently available in the US market for patients with relapsing forms of MS, including interferon beta-1b (Betaseron®4, Extavia®), interferon beta-1a (Avonex®6 and Rebif®), glatiramer acetate (Copaxone8), natalizumab (Tysabri®), fingolimod (Gilenya®), teriflunomide (Aubagio®), dimethyl fumarate (Tecfidera®), alemtuzumab (Lemtrada®), peginterferon beta-1a (Plegridy®), and daclizumab (Zinbryta™). In general, the currently available medications primarily target the mechanisms that underlie inflammation. Early and ongoing treatment helps to minimize early inflammation, reduce damage in nerve fibers (axons), and reduce loss of brain tissue. The anti-inflammatory effects of these agents are largely believed to result from the inhibition of T-lymphocyte proliferation, from a shift of the cytokine response from an inflammatory response to an anti-inflammatory profile, and/or from a reduction in the migration of inflammatory cells across the blood–brain barrier. More recently, ocrelizumab (Ocrevus™) became the first and only DMT approved for the treatment of primary progressive and relapsing forms of MS. Although the precise mechanism by which ocrelizumab exerts its therapeutic effects in MS is unknown, it is presumed to involve the depletion of pre-B and mature B lymphocytes. [paper]
Source: 药渡
Copaxone History
Glatiramer acetate, also known as copolymer-1, is a heterogeneous mixture of peptides comprising 4 amino acids and is similar to myelin basic protein. Copolymer-1 was first discovered in the late 1960s during research to produce an antigen capable of inducing experimental autoimmune encephalomyelitis (EAE), an animal model of MS. [paper]
Following its discovery and the accumulation of preclinical data supporting its use as a therapeutic agent in MS, the clinical evaluation of GA was initiated in the late 1970s. Intensive clinical research has since been conducted on GA to establish its efficacy and safety as a DMT for MS, resulting in its initial approval for RRMS in 1996 and for clinically isolated syndrome (CIS) in 2009, followed by a subsequent label change to the current indication of relapsing forms of MS along with approval of a higher dose and less frequently administered version of GA in 2014. [paper]
Source: Two decades of glatiramer acetate: From initial discovery to the current development of generics
