2017 closes with record approvals of generics, novel drugs; 2018 begins with reprieves for Teva

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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