PharmaCompass wishes its readers a very happy new year. We begin the year with an analysis of 2017, when we saw record approvals of generic drugs, novel drugs and devices. In regulatory inspections, the year saw emergence of a new failing – the improper handling of out-of-specification (OOS) results. There is an update on Teva’s restructuring plans as an Israeli pharmacy chain — Super-Pharm — evinces interest in buying its Ashdod plant. And workers return to work at its tablets factory in Jerusalem after Teva postpones 140 layoffs. There is also news from J&J, which rejigged an old drug, and from Pfizer and Merck who won an FDA nod for selling its late-arrival SGLT2 therapy ertugliflozin in the US.
2017
saw record approvals of generic drugs, novel drugs and devices by the USFDA
The
year gone by saw the highest number of generic drug approvals by the US Food
and Drug Administration (FDA), along with the most ever novel drugs (46); the most ever
novel devices, and the first ever gene therapies.
In
2017, 46 new molecular entities (NMEs) were approved by the FDA , and that excludes the
pathbreaking CAR-T and gene therapies.
The Europe 92 new drugs were recommended for approval, including generics, up from 81 in 2016, and China announced plans to speed up approvals in what is now the world’s second biggest market behind the United States.
In
August, the FDA had approved Novartis’ Kymriah (tisagenlecleucel), the first-ever gene therapy — known as CAR-T (short for chimeric antigen receptor T-cell) — for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL). And in October, the FDA approved the second CAR-T cell therapy — Yescarta (axicabtagene ciloleucel) — for treating adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment.
Until
mid-December, the FDA had approved 765 generic drugs, as opposed to 630 copycats approved in 2016. This made 2017 the industry’s most productive of the last five years. However, analysts warn that 2018 will see more pricing woes for generic companies.
In 2018, PharmaCompass expects to continue
witnessing this activity as the FDA seeks to encourage more competition for generic drugs and works
on accelerating approvals for novel medicines. In December, the FDA provided an
updated list of 319 drugs for which US patents have expired but have no generic
copies.
In 2017, 51 devices received clearance from the FDA. Besides a handful of diagnostic
devices, disease management platforms, and novel monitors, the year also saw
the approval of direct-to-consumer genetic tests for disease risk and a purely
digital intervention.
Medtronic received FDA clearance
for its sensor-enabled single-use vest with 252 electrode sensors that provide
electroanatomic 3D maps of the upper and lower chambers of the heart, and works
by pairing body surface electrocardiogram (ECG) signals from the chest.
The FDA also gave its nod to California-based ResMed’s small and portable continuous positive airway pressure (CPAP) device — AirMini. A non-prescription version of BlueStar (a diabetes management platform from WellDoc) also received the FDA’s nod.
Besides
these devices, a mobile application from Eli Lilly — known as Go Dose — for its rapid-acting insulin Humalog also got a green signal
from the FDA.
VivaLnk,
a Santa Clara-based connected health startup, received FDA clearance for its
first device, a peel-and-stick continuous thermometer for children called Fever
Scout.
2017
saw drop in data-integrity violations, rise in improper handling of OOS results
As we reached 2017-end, we witnessed a reduction in data-integrity violations uncovered at pharmaceutical manufacturers due to the absence of the implementation of audit trail software in quality control testing equipment. However, the implementation of audit trails has resulted in the emergence of a new failing – the improper handling of out-of-specification (OOS) results.
Freseninus’ oncology API plant became the latest facility to be cited for this problem as investigators
found employees had halted and invalidated HPLC (high-performance liquid chromatography)
analyses nearly 250 times when they believed the
tests were going to end with OOS results. The FDA warned Fresenius SE after the company’s Indian plant that makes cancer-drug ingredients for the US market aborted hundreds of drug-quality tests.
We
had found similar observations of improper investigations into OOS results in
warning letters issued to Lupin and Hetero, an EU non-compliance
certificate which was issued to Dr. Reddy’s (DRL) and in the FDA
Form 483 issued to Shilpa Medicare and Baxter’s subsidiary Claris Life Sciences.
Lupin
received a warning letter for its formulation manufacturing facilities in Goa and Indore (Pithampur Unit II). In our review of FDA observations, we found that the company failed to “thoroughly review any unexplained discrepancy” as Lupin invalidated approximately 96 percent of all OOS results obtained at Pithampur and over 75 percent of them in Goa.
In
August, the FDA issued a warning letter to Hetero Labs where it cited
concerns over the quality of products being supplied by Hetero to the United
States. The warning letter highlights that investigations into process
deviations and OOS laboratory results were insufficient, and did not include
scientifically supported conclusions.
At DRL, inspectors from a German regulatory authority concluded that the ‘essential elements of the Pharmaceutical Quality System’ were not effective. Due to this, the plant could not make any further dispatches to the EU until the next inspection. In the case of DRL, the inspectors found that OOS results were “systematically invalidated in hundreds of cases”.
In
December 2016, Baxter had announced the
acquisition of Claris Injectables in India for US$ 625 million. The
Form 483 shared by the FDA of the inspection at Claris site in Ahmedabad raised concerns about “electronic records” that did not match the corresponding environmental monitoring documents.
Teva
postpones 140 layoffs at Jerusalem plant; pharmacy chain to buy Ashdod unit
We have updates on
Israeli generic drug giant Teva Pharmaceutical Industries’ restructuring plan, which had caused a lot of furore in its home country in the last days of
2017. Reports say that Teva will now postpone its layoffs for 140
of the 340 employees at its tablets factory in Jerusalem. These had been
planned for 2018, and have now been postponed until 2019, when all the
remaining workers at the plant will be laid off.
According to news
reports, Teva delayed layoffs amid union strikes and social unrest in Israel. After this announcement, striking employees at Teva’s tablet plant returned to work on January 1. This year, 200 workers at this plant will be laid off.
Last month, Teva
had announced it plans to lay off 14,000 workers worldwide and 1,700 in Israel
as part of its restructuring plan to reduce costs and debts.
There was more reprieve for Teva. Super-Pharm, Israel’s largest pharmacy chain, is in talks to acquire Teva’s plant in Ashdod (a coastal city in Israel). According to a Reuters report, Super-Pharm would pay US$ 17-23 million (60-80 million shekels) to Teva for this plant and is prepared to continue employing the factory’s 70 workers.
“Super-Pharm would be happy to acquire Teva Medical and integrate its workforce. The chain hopes to continue operations in this vital factory, which is responsible among other things for feeding premature babies in hospitals around the country,” Super-Pharm said.
Meanwhile,
a Globes report said Teva’s Assia plant in Petah Tikva (central Israel) will shut down. Of the 140 employees, 100 will be laid off while the
remaining 40 will be transferred to other Teva plants. Teva Assia is engaged in
R&D for generic pharmaceuticals.
Shutting the Assia unit will likely result in a major reduction of the company’s generic R&D, which in turn would reduce the company's ability to develop innovative generic products.
Meanwhile,
the Samuel Neaman Institute found that activity by Teva indirectly contributes five times as much to employment in Israel as to employment at Teva itself. Therefore, according to the Institute, the layoffs by Teva is “a blow to Israel’s economy”.
“The layoffs at Teva are affecting a second and third ring of employment created by the company’s activity, and every person laid off at Teva risks five more layoffs in Israel’s economy,” a report said.
Meanwhile,
Teva’s shareholders are more than satisfied with its new CEO Kare Schultz’s performance so far, says a Globes report. Schultz, a Dane, took over the helm at Teva on
November 1, at a salary of US$ 20 million.
J&J’s rejigged drug for depression offers fast relief, but comes with side effects
Johnson & Johnson has rejigged its old drug — ketamine — and created an intranasal version dubbed esketamine. Ketamine is also the
active ingredient in the mood-altering party drug known as Special K. J&J believes this version is a blockbuster
in the making and one of the biggest potential earners in its late-stage
pipeline.
Esketamine
is a treatment for patients with depression who have failed to benefit from
standard medications.
In
a Phase II study, researchers gave three doses of esketamine to 126 patients,
separating them into three dose groups. The drug performed as expected,
offering a quick uptake over a two-week study with a dose-dependent reaction
that offered fast relief for major depressive disorder.
However, there was both good news and bad news post the trial. First the good news — by day eight, there was a major improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS ) score for the high dose. The MADRS score is based on a psychological questionnaire used by clinicians to assess the severity of depression. For the high dose, the score was more than twice what was registered in the low-dose group — which was also still clinically significant. Over a two-month followup, the response appeared to improve.
Now the bad news — among the side effects was “perceptual changes/dissociative symptoms,” which ran at more than twice the rate seen in the placebo arm. One in four of the patients taking the drug experienced dissociative symptoms. Sedation was another common symptom. The dissociative symptoms occurred shortly after dosing and generally resolved after a couple of hours. In other words, the Phase II version of this drug still carries risks linked to Special K.
Mallinckrodt bags Sucampo for US$ 1.2 billion;
Roche buys Ignyta for US$ 1.7 billion
Global
specialty pharmaceutical company Mallinckrodt closed 2017 with a US$ 1.2 billion buyout of Sucampo, a global biopharmaceutical company. Mallinckrodt will also acquire Sucampo’s commercial and development assets. The transaction was approved by the boards of both the companies.
With
this acquisition, Mallinckrodt hopes to beef up its pipeline of rare disease drugs. The deal delivers one marketed drug — Amitiza (lubiprostone) for constipation — as well as two experimental ones, both in late-stage development.
With
the acquisition of Sucampo, Mallinckrodt gains a late-stage drug for
Niemann-Pick disease type C (NPC), which Sucampo had acquired through its US$
200 million acquisition of Vtesse in April 2017. NPC is a rare progressive genetic disorder
characterized by an inability of the body to transport cholesterol and other
fatty substances (lipids) inside of cell.
Mallinckrodt has made two other acquisitions in recent months — InfaCare (for US$ 425 million) and Ocera (for US$ 117 million).
Roche
to buy Ignyta: Swiss drugmaker Roche will buy Ignyta Inc, an American cancer drug specialist, for US$ 1.7
billion. The deal is aimed at broadening Roche’s oncology portfolio.
Ignyta
will continue its operations in San Diego and will be responsible for the
ongoing pivotal study of entrectinib, its most advanced drug. The company has a
suite of drugs in early stage development that use gene therapy to kill off the
underlying diseases that drive cancer tumor growth. The deal is expected to
close in the first half of 2018.
Merck-Pfizer
make late entry into SGLT2 therapy for diabetes with ertugliflozin
Merck and Pfizer have won an FDA nod for selling ertugliflozin, an SGLT2 (sodium-glucose
cotransporter 2) inhibitor used as therapy for type 2 diabetes. Ertugliflozin is a late arrival
therapy as three other players (J&J, AstraZeneca and Eli Lilly) are deeply
entrenched in the SGLT2 market.
The FDA has posted the approval on its site for ertugliflozin as a single therapy as well as fixed dose combinations with Merck’s Januvia (sitagliptin) or metformin.
Both
Merck and Pfizer will have to maneuver around other key players in the SGLT
inhibitors space. For instance, Eli Lilly won an okay for Jardiance (empagliflozin) three years ago. And then there are other recently launched
type 2 diabetes molecules such as canagliflozin (Invokana
from Janssen Pharmaceuticals) and dapagliflozin (Farxiga from AstraZeneca). Besides, Sanofi and Lexicon plan to pitch their SGLT1/SGLT2 drug sotagliflozin soon.
Back in May 2015, SGLT2 inhibitors such as dapagliflozin, canagliflozin and
empagliflozin received a
setback as the FDA said they may lead to ketoacidosis, a serious condition,
where the body produces high levels of blood acids called ketones, that may
require hospitalization.
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