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Teva Pharmaceotical (3): Decline in Copaxone

Teva Copaxone Sales | Source: Teva quarterly reports

New Dosage by Teva

Teva has been preparing for the entry of generics with a new dosage of three-times-a-week.

In May 2013, Teva announced FDA acceptance of sNDA for Copaxone 40mg/ 1mL, a higher concentration dose of COPAXONE® that offers a less frequent three times a week dosing regimen.

Teva received the approval in January 2014 as previously mention in Copaxone’s history.

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.

First Generic

First generic of Copaxone, Glatopa, was proved in April 16, 2015. 

The approval is for glatiramer acetate in 20 mg/ml daily injections.

Glatopa was developed by Momenta Pharmaceuticals and marketed by Sandoz, a Novartis company.

One month later, the Sandoz launched the drug in the US.

First 40mg/ml Generic Approval

In October 2017, Mylan received the long-waited approval for both dosage versions. Mylan also confirmed the launch in US one day after.

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.

Source: EvaluatePharma

 

Teva Pharmaceutical (2): Reliance on Copaxone

How important is Copaxone to Teva

Revenue 1/5

Copaxone = 21.3% of Teva total revenue in 2013…

  • 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.
  • FDA approved labeling 

court ruling made first generic launch 15 months earlier than expected

Teva Pharmaceutical (1): MS and Copaxone

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]

多发性硬化症（multiple sclerosis，MS）是一种中枢神经系统脱髓鞘疾病，病程中常有缓解复发的神经系统损害症状。多发于青壮年，多数患者是20～40岁的女性。[药事纵横]

在中枢神经纤维外面有一层髓鞘，起着保障神经电信号的正确传导的作用。MS患者的免疫系统会异常地攻击髓鞘，引起炎症，使巨噬细胞“吃掉”髓鞘，中枢神经纤维传导信号的速度和准确度就会受到影响，开始出现神经系统受损的症状。常见的症状有视力下降、复视、肢体感觉障碍、肢体运动障碍、共济失调、膀胱或直肠功能障碍等。[药事纵横]

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]

During 2017 H1, Copaxone sales declined rapidly and made Tecfidera the best-selling drug for MS in 2017.

Available drugs and classification

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

Iran (2): US Pulled Out in 2018 and Now

On May 8, 2018, the United States withdrew from the Joint Comprehensive Plan of Action.

Why

“We cannot prevent an Iranian bomb under the decaying and rotten structure of the current agreement…” “Therefore, I am announcing today that the United States will withdraw from the Iran nuclear deal.”

– Remarks by President Trump on the Joint Comprehensive Plan of Action on May 8, 2018

[Vox] The problem, though, is that the deal wasn’t “rotten”: The best evidence we have suggests Iran was actually complying with the deal. Iran has dismantled a huge portion of its nuclear program and given international inspectors wide latitude to make sure it isn’t cheating; the country is significantly further from a nuclear weapon than it was when the deal came into force.

The rationale:

The first one is that the deal isn’t entirely permanent; the restrictions on Iran’s nuclear program start to relax about 10 years after the deal was signed (though the agreement not to build a nuclear weapon is permanent).

The second is that the deal didn’t cover other problematic things Iran was doing, including ballistic missile development and its support for violent militias around the Middle East (like Hezbollah in Lebanon).

One year after

On 5/8 2019, one year after US President Donald Trump announced his country’s pullout from the Iran nuclear deal, Tehran says it is no longer committed to parts of the agreement. [aljazeera.com]

On 6/13, two tankers were attacked in the Gulf of Oman, a month after four other ships were struck in the region. Tehran has denied any involvement and described them as a false flag operation.

On 6/17, Tehran has sped up the countdown to its breach of the nuclear deal with the announcement that it will exceed its uranium stockpile limit in the next 10 days. The country’s atomic agency also said Tehran might also start the process of enriching uranium up to 20% from 7 July. Kamalvandi, the spokesperson for Iran’s Atomic Energy Organization (AEOI), said Iran needed 5% enrichment for its nuclear power plant in the southern Iranian port of Bushehr and 20% enrichment for a Tehran research reactor.

Iran also announced water supplies at the Arak water reactor would exceed a 130-tonne limit within the next two and a half months if the country did not find a client to buy heavy water byproducts.

On 6/20, a US military surveillance drone has been shot down by Iranian forces while flying over the Strait of Hormuz, one of the world’s most vital shipping routes.

Source: BBC

Iran’s Islamic Revolution Guards Corps (IRGC) said the aircraft had violated Iranian airspace, and that the incident sent a “clear message to America”.

But the US military insisted the drone had been over international waters at the time, and condemned what it called an “unprovoked attack” by the IRGC.

After President Donald Trump’s last-minute pullback from military retaliation, the American focus has shifted to diplomacy and an effort to build international support for Trump’s approach.

Iran (1): the 2015 Deal

A deal, Joint Comprehensive Plan of Action (JCPOA), was reached in 2015 between Iran and P5+1 (US, UK, France, China, Russia and Germany).

The deal came after years of tension over Iran’s alleged efforts to develop a nuclear weapon. Iran insisted that its nuclear programme was entirely peaceful, but the international community did not believe that. [BBC]

A deal summary by Belfer Center for Science and International Affairs, Harvard Kennedy School

Uranium Enrichment

Uranium is required to produce nuclear power and create nuclear weapons. However, the naturally-occurring form of the element does not have a sufficient level of a common fissile isotope U-235 to set off a nuclear reaction.

The amount of U-235 in uranium must be increased through a process of enrichment.

Uranium enriched to between 3 and 4 percent can be used for nuclear power plant fuel, but it must be enriched to around 90 percent for use in weapons.

Iran previously reached a near 20% level enrichment before the deal.

When uranium is mined it typically has about 140 atoms of U-238 for every atom of U-235. Refining it to a purity of 3.67% means using centrifuges to remove 114 unwanted atoms of U-238 for every atom of U-235. Boosting its purity to 20% means removing 22 more unwanted atoms of U-238 per atom of U-235, while going from there to weapons-grade material means removing just four more per atom of U-235. [TheGuardian]

Cap: Stockpile of Low-enriched Uranium

JCPOA set a limit of 3.67 percent enrichment and a stockpile limit of 300kg (660lbs) for 15 years (until 2031).

The United States said in 2015 the deal reduced Iran’s stockpile of enriched uranium by 98 percent, to less than the amount needed for one weapon from enough for about 10. [france24]

Limit: Enrichment capability

Iran had two facilities – Natanz and Fordo – where uranium hexafluoride gas was fed into centrifuges to separate out the most fissile isotope, U-235.

Much of Natanz is deep underground and Fordow is buried inside a mountain, which is widely believed to protect them from aerial bombardment.

The deal allows Iran to continue enrichment at Natanz but with constraints. It turns Fordow into a “nuclear, physics and technology centre” where centrifuges are used for purposes other than enrichment, like producing stable isotopes.

First-generation centrifuges installed in Iran is capped at 6,104, reduced from 19,138.

Plutonium Track

Spent fuel from a heavy-water reactor contains plutonium suitable for a nuclear bomb.

Iran had been building a heavy-water nuclear facility near the town of Arak.

Under the JCPOA, the core of that reactor has been removed and filled with concrete to make it unusable

The reactor is being redesigned so as to “minimise the production of plutonium and not to produce weapon-grade plutonium in normal operation”

Iran will not be permitted to build additional heavy-water reactors or accumulate any excess heavy water until 2031.

Aging Population and % of Healthcare GDP

Here to compare the % of population ages 65 and older and healthcare expenditure as a % of GDP.

United States

1960: 9.1%

2017: 15.4%

The number of Americans ages 65 and older is projected to more than double from 46 million today to over 98 million by 2060, and the 65-and-older age group’s share of the total population will rise to nearly 24 percent from 15 percent.

– prb.org

Healthcare expenditure rose from 5% of GDP in 1960 to 17.9% in 2017.

China

1960: 3.7%

2013: 9%

2017: 10.6%

By 2050, 330 million Chinese will be over age 65.

The population ages 60+ will reach its highest in 2050:  nearly 35%, at 487 million

预计到2025年，我国60岁及以上老年人口数将达到3亿，占总人口的五分之一；到2033年将突破4亿，占总人口的四分之一左右；而到2050年前后将达到4.87亿，约占总人口的三分之一，老年人口数量和占总人口比例双双达到峰值。

Healthcare expenditure mainly ranges from 4% to 5% from 2000 to 2016, rising constantly in recent years. Considering the rapid growth in its GDP, the healthcare expenditure in China is growing fast.

The percentage of GDP is expected to rise to more than 26% for elders’ caring related costs. [2015-2050年，我国用于老年人养老、医疗、照料等方面的费用占GDP的比例将从7.33％升至26.24％]

Just by comparing China to US, China’s healthcare expenditure percentage is a little lagging behind (~10% 65+ population for 7% healthcare GDP). But the opportunity is large as Chinese demographic is changing rapidly. With the historical “one child policy”, China’s working population will experience a “squeeze”.