No­var­tis ad­mits to ‘mis­take’ af­ter par­tial clin­i­cal hold placed on Zol­gens­ma tri­al

No­var­tis on Wednes­day said that the FDA placed a par­tial hold on in­trathe­cal clin­i­cal tri­als of its gene ther­a­py Zol­gens­ma (onasemno­gene abepar­vovec-xioi) for spinal mus­cu­lar at­ro­phy (SMA) pa­tients based on find­ings in a small pre­clin­i­cal an­i­mal study.

On Thurs­day, a No­var­tis spokesper­son told Fo­cus that a draft re­port of the pre­clin­i­cal safe­ty find­ings was pre­sent­ed to the AveX­is safe­ty man­age­ment team last March and the com­pa­ny “de­ter­mined at that time that the safe­ty find­ing should be in­clud­ed in the an­nu­al up­date of the in­ves­ti­ga­tor brochure planned for Sep­tem­ber 2019. Un­for­tu­nate­ly, a mis­take was made, and this up­date was not im­ple­ment­ed.”

The omis­sion was lat­er iden­ti­fied as part of a No­var­tis re­view re­lat­ed to the Form 483 re­sponse from Au­gust, and the spokesper­son told Fo­cus, “This omis­sion was iden­ti­fied and the is­sue quick­ly as­sessed and man­aged pur­suant to ex­ist­ing No­var­tis safe­ty process­es and we no­ti­fied health au­thor­i­ties and clin­i­cal tri­al in­ves­ti­ga­tors.”

But the spokesper­son al­so said that No­var­tis no­ti­fied in­ves­ti­ga­tors and the FDA at the end of last week on the find­ings and was no­ti­fied about the par­tial clin­i­cal hold ear­li­er this week.

The com­pa­ny al­so stressed that the par­tial hold does not im­pact the mar­ket­ing of Zol­gens­ma or some oth­er clin­i­cal tri­als.

“This was a small, AveX­is-ini­ti­at­ed pre-clin­i­cal study in which an­i­mal find­ings showed dor­sal root gan­glia (DRG) mononu­clear cell in­flam­ma­tion, some­times ac­com­pa­nied by neu­ronal cell body de­gen­er­a­tion or loss. The tri­al in­volved 12 non-hu­man pri­mates,” the No­var­tis spokesper­son said.

The clin­i­cal sig­nif­i­cance of the DRG in­flam­ma­tion ob­served in this pre-clin­i­cal an­i­mal study is not known and was not seen in pri­or an­i­mal stud­ies, the com­pa­ny added. “We will con­tin­ue to close­ly mon­i­tor for any re­ports of re­lat­ed safe­ty events in pa­tients,” No­var­tis said. “We will work dili­gent­ly with FDA to iden­ti­fy any ad­di­tion­al ac­tions nec­es­sary to re­sume dos­ing in the AVXS-101 in­trathe­cal clin­i­cal tri­als.”

In Au­gust, No­var­tis ran in­to trou­ble with the FDA when da­ta ma­nip­u­la­tion was un­cov­ered in the Zol­gens­ma ap­pli­ca­tion, al­though the ma­nip­u­la­tion did not af­fect the FDA’s as­sess­ment of the gene ther­a­py’s safe­ty or ef­fi­ca­cy. Ques­tions re­lat­ed to the time­line of the un­cov­er­ing of the ma­nip­u­la­tion were al­so raised.

RAPS: First pub­lished in Reg­u­la­to­ry Fo­cus™ by the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety, the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care prod­ucts. Click here for more in­for­ma­tion.


Zachary Brennan

managing editor, RAPS

Lessons for biotech and phar­ma from a doc­tor who chased his own cure

After being struck by a rare disease as a healthy third year medical student, David Fajgenbaum began an arduous journey chasing his own cure. Amidst the hustle of this year’s JP Morgan conference, the digital trials platform Medable partnered with Endpoints Studio to share Dr. Fajgenbaum’s story with the drug development industry.

What follows is an edited transcript of the conversation between Medable CEO Dr. Michelle Longmire and Dr. Fajgenbaum, and it is full of lessons for biotech executives charged with bringing the next generation of medicines to patients.

No­var­tis gets a boost in block­buster mul­ti­ple scle­ro­sis race with Roche

In the first step of what’s likely to be a long and uphill battle for the drugmaker, the FDA has accepted Novartis’s BLA submission for a new multiple sclerosis drug and given it priority review. The PDUFA date for the potential blockbuster drug is in June.

The drug, known as ofatumumab or Arzerra, has performed consistently well across late-stage trials in patients with the most common form of MS, including in head-to-head studies against Sanofi’s old blockbuster Aubagio. But, if the drug is approved, Novartis will find itself in a crosstown game of catch-up; since a 2017 approval, Roche’s Ocrevus has become the second best-selling MS drug on the market, nearly eclipsing Biogen’s Tecfidera last quarter with over a $1 billion in sales.

Coro­n­avirus out­break threat­ens short­age of 150 drugs — re­port

American patients who suffer from conditions other than Covid-19 could feel the impact of the coronavirus due to shortage of drugs — as 150 prescription drugs are now reportedly on a list of at-risk therapies. The list spans “antibiotics, generics and some branded drugs without alternatives,” Axios reported citing sources familiar with the list. The FDA declined to comment.

Although factories in China are gradually reopening, restrictions in travel and disruptions at transit hubs are still slowing down production. An Indian company that relies on active pharmaceutical ingredients (API) from China told Bloomberg last week that it’s seeing prices of commonly used drugs jump by 40% to 70%.

Juergen Horn

An­i­mal health vet Juer­gen Horn makes new an­ti­body play for pets, rak­ing $15M in Se­ries A haul

Zoetis forked over $85 million in 2017 to acquire Nexvet Biopharma and its pipeline of monoclonal antibodies. Juergen Horn, Nexvet’s former chief product development officer, has now secured $15 million for his own biologic company for animals: Invetx.

Buoyed by emerging advances in gene therapies for humans, scientists have started looking at harnessing the technology for animals setting up companies such as Penn-partnered Scout Bio and George Church-founded Rejuvenate Bio. But akin to Nexvet, Invetx is working on leveraging the time-tested science of monoclonal antibodies to treat chronic diseases that afflict man’s best friend.

Tim Mayleben (file photo)

Es­pe­ri­on's goldilocks cho­les­terol fight­er wins FDA ap­proval — will its 'tra­di­tion­al' pric­ing ap­proach spur adop­tion?

It’s more effective than decades-old statins but not as good as the injectable PCSK9 — the goldilocks treatment for cholesterol-lowering, bempedoic acid, has secured FDA approval.

Its maker, Esperion Therapeutics, is betting that their pricing strategy — a planned list price of between $10 to $11 a day — will help it skirt the pushback the PCSK9 cholesterol fighters, Repatha and Praluent, got from payers for their high sticker prices.

The sky-high expectations for the pair of PCSK9 drugs that were first approved in 2015 quickly simmered — and despite a 60% price cut, coupled with data showing the therapies also significantly cut cardiovascular risk, sales have not really perked up.

Esperion is convinced that by virtue of being a cheaper oral therapy, bempedoic acid will hit that sweet spot in terms of adoption.

“We’re kind of like the old comfortable shoe,” Esperion’s chief commercial officer Mark Glickman remarked in an interview with Endpoints News ahead of the decision date. “It’s an oral product, once-daily and nontitratable — these are things that just resonate so true with patients and physicians and I think we’ve kind of forgotten about that.”

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As coro­n­avirus out­break reach­es 'tip­ping point,' GSK lends ad­ju­vant tech to Chi­nese part­ner armed with pre­clin­i­cal vac­cine

As the coronavirus originating out of Wuhan spreads to South Korea, Italy and Iran, stoking already intense fears of a pandemic, GlaxoSmithKline has found another pair of trusted hands to place its adjuvant system. China’s Clover Biopharmaceuticals will add the adjuvant to its preclinical, protein-based vaccine candidate against SARS-CoV-2.

Clover, which is based in the inland city of Chengdu, boasts of a platform dubbed Trimer-Tag that produces covalently-trimerized fusion proteins. Its candidate, COVID-19 S-Trimer, resembles the viral spike (S)-protein found in the virus.

Deborah Dunsire

The fourth CGRP mi­graine drug is here. Time for Lund­beck to prove it's worth $2B

They may be late, but Lundbeck is now officially in the game for preventing migraine with CGRP drugs.

The FDA has OK’d eptinezumab, the prize in Lundbeck’s $2 billion acquisition of Alder. Like rival offerings from Amgen/Novartis, Eli Lilly and Teva, the antibody blocks the calcitonin gene-related peptide, which is believed to dilate blood vessels in the brain and cause pain.

It will now be sold as Vyepti. The company has yet to announce a price. Amgen and Novartis had set the wholesale acquisition cost of their pioneering Aimovig at $6,900 for a year’s supply before raising it slightly this year; Lilly and Teva had followed suit with Emgality and Ajovy.

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Tal Zaks (Moderna via YouTube)

For two decades, a new vac­cine tech­nol­o­gy has been slow­ly ap­proach­ing prime time. Now, can it stop a pan­dem­ic?

Two months before the outbreak, Moderna CMO Tal Zaks traveled from Cambridge, MA to Washington DC to meet with Anthony Fauci and the leaders of the National Institutes of Health.

For two years, Moderna had worked closely with NIH researchers to build a new kind of vaccine for MERS, one of the deadliest new viruses to emerge in the 21st century. The program was one test for a new technology designed to be faster, cheaper and more precise than the ways vaccines had been made for over a century. They had gathered evidence the technology could work in principle, and Fauci, the longtime head of the National Institute of Allergy and Infectious Diseases and a longtime advocate for better epidemic preparedness, wanted to see if it, along with a couple of other approaches, could work in a worst-case scenario: A pandemic.

“[We were] trying to find a test case for how to demonstrate if our technology could rapidly prepare,” Zaks told Endpoints News.

Zaks and Fauci, of course, wouldn’t have to wait to develop a new test. By year’s end, an outbreak in China would short circuit the need for one and throw them into 24/7 work on a real-world emergency. They also weren’t the only ones with new technology who saw a chance to help in a crisis.

An ocean away, Lidia Oostvogels was still on vacation and relaxing at her mother’s house in Belgium when her Facebook started changing. It was days after Christmas and on most people’s feeds, the news that China had reported a novel virus to the World Health Organization blurred into the stream of holiday sweaters and fir trees. But on Oostvogels’s feed, full of vaccine researchers and virus experts, speculation boiled: There was a virus in China, something contained to the country, but “exotic,” “weird,” and maybe having to do with animals. Maybe a coronavirus.

Lidia Oostvogels

“I was immediately thinking like, ‘Hey, this is something that if needed, we can play a role,'” Oostvogels told Endpoints.

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Drug ap­provals: FDA pub­lish­es dataset of CDER ap­provals since 1985

To provide researchers with more accurate and accessible data about historic drug approvals, the FDA on Friday released a dataset containing information about all new drugs and biologics approved by the Center for Drug Evaluation and Research (CDER) dating back to 1985.

“FDA created the compilation to facilitate data accessibility, transparency, and accuracy when researchers seek information about an approved drug,” the FDA writes, adding that the compilation should accurately reflect “the state of each application at the time of initial regulatory approval.”