Four new U.S. drug approvals, one accelerated for need, have handed a string of year-end victories to five drugmakers, marking an unusually active start to a week full of global holiday celebrations. Daiichi Sankyo Co. Ltd., Astrazeneca plc, Eisai Inc., Intra-Cellular Therapies Inc. and Allergan plc all secured new approvals from the agency. Daiichi's Enhertu (trastuzumab deruxtecan), the subject of a $6.9 billion deal with Astrazeneca, won accelerated approval for the third-line treatment of adults with unresectable or metastatic HER2-positive breast cancer. Eisai's Dayvigo (lemborexant) was approved to treat insomnia. Intra-Cellular's Caplyta (lumateperone) was approved to treat schizophrenia. Allergan’s Ubrelvy (ubrogepant) became the first of a relatively new class of drugs to be approved for the acute treatment of migraine.

Ahead of schedule

Enhertu, approved nearly four months ahead of expectations, is so far the only one to rate public comment from the FDA. The regulator's cancer drugs chief, Richard Pazdur, cited the "many advances in the development of drugs for HER2-positive breast cancer since the introduction of Herceptin (trastuzumab) in 1998" and the improvements in scientific understanding of targeted therapies for malignant diseases that underpinned the antibody-drug conjugate's development.

In particular, Enhertu's approval delivers a new option for treating low-expressing as well as high-expressing HER2 tumor types, even those across a spectrum beyond metastatic breast cancer that includes gastric, colorectal and non-small-cell lung cancers. Need is especially acute in low-expressing HER2s, where broad potential for the medicine compelled Cambridge, U.K.-based Astrazeneca to pay Daiichi $1.35 billion up front and pledge up to $5.55 billion in additional payments to its Tokyo-headquartered partner under the terms of their April 2019 deal. U.S. approval of the drug triggered a $125 million milestone payment for Daiichi from Astrazeneca.

In a trial that enrolled 184 women with heavily pretreated HER2-positive, unresectable and/or metastatic breast cancer, those receiving Enhertu had an overall response rate of 60.3% and a median duration of response of 14.8 months. The drug's label includes a boxed warning advising of the risk of interstitial lung disease and embryo-fetal toxicity.

Separately, Astrazeneca said Monday that China's National Medical Products Administration had approved its triple-combination therapy (glycopyrrolate + formoterol fumarate + budesonide) for the maintenance treatment of chronic obstructive pulmonary disease. COPD affects almost 100 million people in China and is a leading cause of morbidity and mortality, according to the company. The medicine, which remains under regulatory review in the U.S. and EU, was approved in Japan in June as Breztri Aerosphere.

Less lost sleep

Eisai's Dayvigo, a dual orexin receptor antagonist, will offer U.S. health care providers a new tool in addressing insomnia, a common sleep problem affecting as many as 30% of adults, according to the National Sleep Foundation.

Though the drug is not without risks, the Tokyo-based company highlighted Dayvigo's overall safety in its announcement of the approval, pointing to both freedom from ill effects of discontinuation and benefits for postural stability and cognitive performance among those receiving the drug in pivotal trials. The postural element could be of particular importance for the elderly in reducing the risk of nighttime falls, the company told BioWorld earlier this year. The drug will also provide insomniacs with a new alternative to opioids, which are sometimes used by the sleepless to find rest.

The approval was based on data that included two pivotal phase III studies that found Dayvigo demonstrated statistically significant superiorities on sleep onset and sleep maintenance vs. placebo as recorded by multiple measures.

Dayvigo is the product of what was a long-running partnership between Eisai and troubled opioid maker Purdue Pharma LP, now in bankruptcy. In April, the former partners parted ways, with Eisai buying out Purdue's rights to the worldwide collaboration for the development and commercialization of Dayvigo.

A volatile response

Shares of Intra-Cellular Therapies Inc. (NASDAQ:ITCI), which had been relatively depressed following a late-summer announcement of a three-month extension for FDA review of its schizophrenia treatment, Caplyta, soared Monday morning, climbing $24.07, or 193.5%, to close at $36.51 despite briefly hitting a Nasdaq trading halt for volatility.

Despite the earlier delay, FDA approval for the multimechanism medicine, licensed to Intra-Cellular by Bristol-Myers Squibb Co. in 2005, arrived several days ahead of its Dec. 27 PDUFA date. The approval triggers a $2 million milestone payment due to BMS from New York-based Intra-Cellular.

Caplyta's efficacy was demonstrated in two placebo-controlled trials, showing a statistically significant separation from placebo on the primary endpoint, the Positive and Negative Syndrome Scale (PANSS) total score. The most common adverse reactions vs. placebo were somnolence, sedation and dry mouth.

The drug’s label includes a boxed warning advising that elderly patients with dementia-related psychosis treated with antipsychotic drugs given Caplyta are at increased risk of death.

With a similar clinical benefit in the ongoing head-to-head trials vs. Johnson & Johnson's Risperdal (risperidone), while maintaining that drug's metabolic profile, Caplyta has the potential to become preferred maintenance therapy in schizophrenia, according to Cortellis. Intra-Cellular expects to initiate the commercial launch of Caplyta late in the first quarter of 2020.

No pain

For Allergan, the Dublin-based drugmaker in the sights of North Chicago-based Abbvie Inc., Monday also brought good news. The FDA’s approval of Ubrelvy made the oral calcitonin gene-related peptide (CGRP) receptor antagonist first-to-finish among companies developing candidates in the class poised to treat acute migraines, with or without aura. Migraine afflicts 31 million Americans, the company said, a fact that has made the indication a rich target for a host of competitors. The painful and disabling condition is three times more common in women than in men, the FDA said.

The new drug, first developed Merck & Co. Inc. as MK-1602, was licensed by Allergan with another CGRP receptor agonist from the company in July 2015 for up-front payments of $250 million. Under the agreement, Merck was entitled to $350 million in R&D and approval milestones. The deal also included $430 million in potential development and commercial milestone payments and royalties at tiered double-digit rates. Most recently, Allergan reported having paid Merck $115 million in connection with those obligations during 2018.

Efficacy of Ubrelvy was demonstrated in two randomized, double-blind, placebo-controlled trials in which more than 1,400 adults with a history of migraine participated. In both studies, the percentages of patients who saw their headache severity fall from moderate or severe pain to no pain and whose most bothersome migraine symptom stopped two hours after treatment were significantly greater among patients receiving Ubrelvy as compared to those receiving placebo.

The most common side effects that patients in the clinical trials reported were nausea, tiredness and dry mouth.

Pricing for the newly approved medicines was not initially disclosed.

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