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26 May, 2021
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FDA closes the door on EUA requests for some future Covid-19 vaccines
2.
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‘Inaccuracies’ push FDA to reverse Trump-era termination of its Unapproved Drugs Initiative
3.
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FDA may require bispecific antibodies to be compared with monospecific products
4. Opinion: It shouldn’t matter who the FDA commissioner is when it comes to controversial drug approval decisions
5. UPDATED: FDA revises and expands draft guidance on adjusting for covariates in RCTs
6. US pauses distribution of Lilly mAb combo to Massachusetts due to Covid-19 variant
7. UPDATED: J&J beats Tagrisso and Takeda to the punch in key NSCLC subset, picking up new FDA approval
8. Bristol Myers' Opdivo leads the pack with FDA approval for resected esophageal or GEJ cancer
9. Bluebird’s new gene therapy among three new EMA OKs ahead of FDA
10. Deaths of monkeys spur clinical hold for rare disease biotech's lead and only drug — and a $95M cash infusion goes out the window
11. Provention Bio rollercoaster continues with generally positive remarks from FDA ahead of Thursday’s adcomm
12. FDA adcomm to review FibroGen’s chronic kidney disease drug in July
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Zachary Brennan
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Still no FDA commissioner nominee but the agency is churning along at a much faster clip than we saw at the beginning of this administration. Stay tuned for much more analysis and insider fun at the FDA. As always, feel free to respond directly to this email with any thoughts or comments.

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Zachary Brennan
Senior Editor, Endpoints News
@ZacharyBrennan
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Peter Marks (Susan Walsh/Pool via AP Images)
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1
by Zachary Brennan

The FDA late Tuesday said that for the remainder of the pandemic, it may decline to review and process further EUA requests for Covid-19 vaccines, unless a developer has already engaged with the agency.

The move ostensibly will push later Covid-19 vaccine entrants to go the long route and submit a full BLA with more manufacturing and safety data rather than use the shortened EUA process.

The decision also comes as Pfizer has already submitted its full BLA to the FDA (and Moderna will soon follow suit), and FDA's top vaccine official Peter Marks previously told Endpoints News that it may only take a few months to review those applications.

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2
by Zachary Brennan

Due to “multiple legal and factual inaccuracies,” the Biden administration’s FDA said Wednesday that it will reverse the Trump-era decision to pull the agency’s controversial Unapproved Drugs Initiative.

The decision to withdraw the Trump HHS notice terminating the initiative comes as Biden’s FDA says it was never consulted on the decision in the first place, and it does not accurately reflect HHS’ or FDA’s thinking “because it is inconsistent with the FD&C Act, FDA regulations, and judicial precedent, among other legal authorities, and is not supported by the facts,” according to a Federal Register posting on Wednesday.

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3
by Zachary Brennan

With about 100 bispecific antibodies either in clinical trials or soon entering, the FDA on Monday updated and finalized its guidance on developing bispecific antibodies, clarifying how it may require clinical trials to compare the bispecifics with an approved monospecific product.

In the era of immunotherapies, the case for bispecifics hinges on their ability to improve on monoclonal antibodies and more directly target cancer tumor cells, among other potential indications. Companies are already seeing some payoff, like Amgen’s bispecific Blincyto, which first won approval in 2018 and brought in about $380 million last year.

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by Zachary Brennan

Several years ago, I interviewed for a job and the employer asked me to explain something shocking about the FDA that the general public either doesn’t know or wouldn’t understand.

I thought for a minute and said, “The FDA commissioner doesn’t weigh in on any drug approval decisions.” And the interviewer looked at me quizzically, and said something along the lines of, “That can’t be right.”

While my comment may have been a bit hyperbolic, I was reminded of this moment recently when I saw a headline in Fortune on Tuesday proclaiming, “President Biden still hasn’t appointed a permanent FDA commissioner. That has big implications for upcoming drug approvals.”

Indeed, it’s true, the permanent FDA commissioner nomination still hasn’t arrived from the Biden administration – 126 days after he was inaugurated, and there's no indication that a nominee is incoming. But that doesn’t mean much of anything for contentious drug approval decisions coming soon, especially for Biogen’s potential Alzheimer’s drug aducanumab, which is due for a verdict by June 7.

As FDA officials have pounded into my head over the years, and as a former senior FDA official confirmed again recently, the FDA commissioner and the Office of the Commissioner have no place at the table when the agency signs off on any controversial approvals or CRLs.

Why? Because political appointees should rely on the experienced career scientific staff, well-established processes and lines of command to make such decisions based on the evidence at hand. It's the same reason that former President Trump shouldn't have pressured the FDA to speed up its review of any Covid-19 vaccine EUAs.

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5
by Zachary Brennan

The FDA on Thursday revised and expanded a 2019 draft guidance that spells out how to adjust for covariates in the statistical analysis of randomized controlled trials (RCTs).

Building on the ICH’s E9 guideline on the statistical principles for clinical trials, the 3-page draft has been transformed into an 8-page draft, with more detailed recommendations on linear and nonlinear models to analyze the efficacy endpoints in RCTs.

Baseline covariates are the demographic factors, disease characteristics, or other information collected from participants before they are randomized in a trial, FDA explains. “Covariate adjustment refers to the use of baseline covariate measurements for estimating and testing treatment effects between randomized groups,” the guidance notes.

Such adjustments will generally reduce the variability of estimating treatment effects and lead to narrower confidence intervals and more powerful hypothesis testing.

While linear models are regarded by FDA as generally providing “reliable estimation and inference for the average treatment effect,” additional issues should be considered before sponsors use nonlinear models, the guidance says.

“Sponsors should discuss with the relevant review divisions specific proposals in a protocol or statistical analysis plan containing nonlinear regression to estimate conditional treatment effects for the primary analysis,” FDA says. “When estimating a conditional treatment effect through nonlinear regression, the model will generally not be exactly correct, and results can be difficult to interpret if the model is misspecified and treatment effects substantially differ across subgroups.”

The revised draft also features an example of six steps for one statistically reliable method of covariate adjustment for an unconditional treatment effect with binary outcomes that produce a resulting estimator.

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6
by Zachary Brennan

Now that the CDC has found that the Covid-19 variant originally identified in Brazil is circulating with a frequency exceeding 10% in Massachusetts, the US has halted shipments of Eli Lilly's monoclonal antibody combo treatment because it's not active against this variant.

The FDA recommends that health care providers in Massachusetts use Regeneron's monoclonal antibody as an alternative to Lilly's therapy until further notice.

Massachusetts is the second state to see a rise in the Brazilian variant, known as P.1, so far. Earlier this month, the US also paused shipments of the Lilly treatment to Illinois.

"The P.1 variant has been persistently elevated at a frequency exceeding 20% in Illinois, and the shipping restriction to Illinois remains in effect," the Assistant Secretary for Preparedness and Response said in a statement. ASPR and FDA said they will continue to work with the CDC and the National Institutes of Health on surveillance of variants that may impact the use of the monoclonal antibody therapies authorized for emergency use.

A Lilly spokesperson previously explained how the majority of variants currently circulating in the US are neutralized by the company's combo of bamlanivimab and etesevimab together. The prevalence of certain variants can also change rapidly.

Last month, FDA revoked the EUA for Lilly’s bamlanivimab alone, which it said is no longer as effective as the combo therapy because of this rise in coronavirus variants.

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7
by Max Gelman

Looking to outflank AstraZeneca’s best-selling drug in a non-small cell lung cancer niche, J&J scored an important approval Friday afternoon.

Regulators gave the thumbs-up to Janssen’s amivantamab for the treatment of metastatic NSCLC with EGFR exon 20 insertion mutations, the FDA announced Friday. It’s the first drug approved to treat such patients, with J&J planting a stake in a part of the EGFR mutation arena where its competitors have struggled to gain a foothold.

The drug, whose approval comes after J&J jumped straight from a Phase I study to a BLA priority review, will be branded as Rybrevant. In an emailed statement to Endpoints News, J&J declined to comment on specific pricing for the drug, saying only that it would "reflect its incremental value" in NSCLC outcomes for this population and be "comparable to other infused oncology medicines."

While lung cancer is the most common form of cancer and is the leading cause of worldwide cancer deaths, patients with EGFR exon 20 insertion mutations had been excluded from taking previously approved drugs — only about 2% to 3% of NSCLC patients have these mutations, the FDA said. That list includes AstraZeneca’s blockbuster Tagrisso, which raked in more than $4 billion last year.

Tagrisso is only OK’ed for exon 19 deletions or exon 21 L858R mutations, or patients with EGFR mutations who had undergone tumor resection and optional, standard postoperative adjuvant chemotherapy.

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8
by Zachary Brennan

In a first for immunotherapies, Bristol Myers Squibb’s PD-1 blockbuster Opdivo (nivolumab) won another FDA approval on Thursday, this time for the adjuvant treatment of completely resected esophageal or gastroesophageal junction (GEJ) cancer with residual pathologic disease in patients who have received neoadjuvant chemoradiotherapy.

The approval is based on the results from a placebo-controlled, Phase III trial in 794 patients, demonstrating a statistically significant improvement in disease-free survival (DFS), which was defined as the time between randomization and the first recurrence date, or death, from any cause.

“The median DFS was 22.4 months (95% CI: 16.6, 34.0) versus 11 months (95% CI: 8.3, 14.3), respectively (HR 0.69; 95% CI: 0.56, 0.85; p=0.0003). The DFS benefit was observed regardless of tumor PD-L1 expression and histology,” FDA said.

Esophageal cancer is the seventh most common cancer and the sixth leading cause of death from cancer worldwide, with approximately 572,000 new cases and over 508,000 deaths in 2018, according to BMS. The company said Opdivo has now won approval for 22 indications across 11 types of cancer.

The approval comes as BMS saw disappointing sales for Opdivo in the first quarter, down 3% from the same time period last year at $1.72 billion, according to earnings from late April. But Opdivo is being studied in several late-stage trials, showing benefit in resectable patients across a range of tumor locations, including bladder cancer and melanoma. Those expanding data sets could position Opdivo well to take a leading position in resectable cancers over its other highly-touted rivals, Opdivo head of development Mark Rutstein told Endpoints News last month.

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9
by Zachary Brennan

Ahead of a usually speedy FDA, the European Medicines Agency on Friday recommended marketing authorizations for bluebird bio’s new gene therapy for children with a rare, inherited neurological disease, GlaxoSmithKline and Vir’s monoclonal antibody treatment for Covid-19, and a new treatment for a rare liver disease.

In the case of bluebird’s Skysona (elivaldogene autotemcel), the gene therapy is for those younger than 18 who have what’s known as early Cerebral Adrenoleukodystrophy (CALD). If untreated, nearly half of those with CALD die within 5 years of symptom onset, EMA said.

EMA’s recommendation is based on a single-arm trial in 32 boys with CALD (the disorder is almost exclusively seen in males) who received the one-time treatment, compared to 59 boys who had a stem cell transplantation.

“An analysis conducted after 24 months from the infusion on 30 subjects enrolled in the study concluded that for 27 of them (90%) treatment with Skysona preserved motor function and communication ability and improved survival when compared to untreated patients at an early stage of cerebral disease,” the EMA said.

Bluebird bio said it is currently on track to submit the Biologics License Application to the FDA by mid-2021.

Richard Colvin, interim CMO at bluebird, said in a statement, “This positive opinion from the CHMP marks the first regulatory approval recommendation for any gene therapy for CALD, bringing us closer to a one-time, durable treatment option that stabilizes neurological disease while reducing the risk of the serious immune complications associated with allogeneic stem cell transplantation (allo-HSCT), which is the only therapeutic option for children with this devastating disease.”

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Carole Ben-Maimon
10
by Amber Tong

In the world of small public biotechs, one mishap can be punishing.

Just ask Larimar Therapeutics, which disclosed late Tuesday that the FDA has placed a clinical hold on its Phase I drug for Friedreich’s ataxia following deaths of non-human primates in a toxicology study.

The surprise setback scuttled plans for a $95 million private financing that would’ve drawn in new cash from marquee investors like Deerfield, RA Capital, Cowen Healthcare Investments, Vivo Capital, Surveyor Capital (a Citadel company), Adage Capital Management and Verition Fund Management. Shares LRMR plunged 45.23% to $7.40 in after-hours trading.

It also marks the biggest crisis for the company since it rode Zafgen's shell to Nasdaq in December 2019. Previously named Chondrial Therapeutics, Larimar has essentially been staking its entire business on its lead drug in hopes that it would become a poster child for the protein replacement therapies to come on its platform, with a special focus on rare diseases characterized by deficiencies in intracellular compounds.

The non-human primates that died — Larimar didn’t specify how many — had been given the highest doses of CTI-1601, a recombinant fusion protein designed to deliver human frataxin into the mitochondria, as part of a study around extended dosing of the drug. Patients with FA are unable to produce enough of the protein, which is essential for metabolic functions.

Regulators now want Larimar to finish the 180-day NHP study and submit a “full study report” before it can initiate any new clinical trials.

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11
by Zachary Brennan

Early last month, Provention Bio's shares cratered after disclosing that the FDA found the pharmacokinetic profiles of its potential type 1 diabetes drug, acquired from Eli Lilly, differed when manufactured by Lilly versus Provention.

At the time, the FDA said its concerns meant that it was not ready to start post-marketing and label discussions with the company.

But now, two days ahead of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee meeting to discuss the drug, known as teplizumab, the FDA sounded a relatively positive tone on safety and efficacy. The company’s stock was up about 30% early Tuesday.

While noting some missing data from the company’s trials, the FDA said Tuesday that “because the amount of missing data was small, sensitivity analyses performed using different missing data handling approaches show that the observed efficacy by the primary analysis method is sufficiently robust to withstand conservative approaches in handling missing data.”

The question of what constitutes substantial evidence of effectiveness will be top of mind for the committee to address, FDA notes, explaining how Provention submitted a relatively small, single placebo-controlled trial with the primary endpoint of delay of clinical type 1 diabetes, as well as additional data, which FDA said can be used as “confirmatory evidence.”

On safety, the briefing documents did not reveal any glaring red flags, although the agency noted that "slightly more than 10% of patients" in the trial "were not able to receive the full course of teplizumab secondary to meeting protocol-specified withdrawal criteria."

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Enrique Conterno, FibroGen CEO
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by Zachary Brennan

The FDA said Thursday that its Cardiovascular and Renal Drugs Advisory Committee of outside experts will convene on July 15 to review the safety and efficacy of FibroGen’s potential treatment for anemia in chronic kidney disease.

The drug, known as roxadustat, has been hit with cardiovascular safety questions recently as the company had to double back and inform the FDA of some post-hoc changes. The announcement that an advisory committee would be necessary, which came in early March, also was a surprise.

“As members of senior management were preparing for the upcoming FDA Advisory Committee meeting, we became aware that the primary cardiovascular safety analyses included post-hoc changes to the stratification factors,” said CEO Enrique Conterno in April. “While all of the analyses set forth below, including the differences in the stratification factors, were included in the NDA, we promptly decided to clarify this issue with the FDA and communicate with the scientific and investment communities.”

Wall Street biotech analysts and others like the Institute for Clinical and Economic Review (ICER) remain mixed on the drug overall.

Michael Yee at Jefferies thought the changes announced in April were an issue, noting: “Bottom line is while overall the stats don’t have a huge change and the co believes conclusions still support an FDA approval – we believe the fact that Incident Dialysis is no longer ‘statistically’ superior – is a material change to the profile and one of the key prior advantages for .”

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