Asco 2020 – after Tecentriq’s liver win the spotlight falls on Merck and Astra

Roche secures a front-line liver cancer label, but rival data at Asco show that the competition isn’t resting on its laurels.

Today’s US approval for Roche’s Tecentriq/Avastin combo, backed by overall survival in the Imbrave-150 trial, marks a first for immunotherapy in first-line liver cancer.
It also boosts Roche’s Avastin lifecycle strategy, as well as enabling the group to leapfrog Merck & Co and Bristol-Myers Squibb, whose Keytruda and Opdivo both carry liver cancer labels but only in the second-line setting. Bristol failed in Checkmate-459, a front-line Opdivo monotherapy study, however Roche’s lead might not last long.
Judging by data presented at Asco over the weekend, front-line liver cancer competition could be around the corner. The next threat could come from Astrazeneca, which hopes to report the findings of the first-line Himalaya study later this year.
This tests Imfinzi monotherapy, or in two combinations with the anti-CTLA-4 agent tremelimumab, against Nexavar; the primary outcome is overall survival, though it is not clear how the statistical powering is being split across the trial’s various cohorts.
At Asco Astra provided a way of handicapping Himalaya, courtesy of a phase II trial called Study 22. This enrolled a mixture of first and second-line subjects, and though it effectively had no control cohort it did provide backing of sorts for the Imfinzi/tremelimumab combo.

Overall survival in Study 22. T300+D = 300mg tremelimumab + Imfinzi. Source: Dr Katie Kelley & Asco.

This fact alone puts study 22 in a rare category of trials in which tremelimumab has not been a flop. The cohorts tested in the study were two regimens of the combo, as well as Imfinzi or tremelimumab as monotherapies, all after a limited run-in period on the combo.
The highlight was that the best median overall survival, 18.7 months, was seen in patients given Imfinzi plus 300mg tremelimumab – the same regimen that is being tested in one of the arms of Himalaya.
Curiously, tremelimumab monotherapy yielded the second-best mOS figure, 15.1 months, but the baseline characteristics were imbalanced: only 44% of treme monotherapy subjects were second-line, versus 57% of those on the combo. The presenters also said study 22 showed remissions regardless of subjects’ PD-L1 status.
For its part, Merck is relying on Eisai’s Lenvima as the other half of its Keytruda combination in front-line liver cancer; its pivotal Leap-002 study of this approach compared with Lenvima monotherapy reads out in 2022.

Remissions in Keynote-524, per Recist 1.1. Source: Dr Andrew Zhu & Asco.

At Asco Merck presented a poster on Keynote-524, a small uncontrolled trial of Keytruda plus Lenvima. This yielded 22.0 months of mOS, and 36 of the 100 subjects experienced disease remission. Though this was only a phase I trial it effectively represented the front-line setting, as subjects could not have received prior systemic therapy.
The one caveat for Merck is that its second-line label, backed by an accelerated approval, looks questionable after last year’s failure of the confirmatory phase III trial Keynote-240. Roche therefore has a lot going for its Avastin combo, but it must make the most of its window of opportunity.

Immunotherapy in hepatocellular carcinoma
	Bristol-Myers Squibb	Merck & Co	Astrazeneca	Roche
1st-line	Opdivo vs Nexavar failed CM-459 study	Keytruda + Lenvima combo in Leap-002 study (ends 2022)	Imfinzi + tremelimumab combo in Himalaya study (ends 2020)	Tecentriq + Avastin combo approved Jun 2020 (Imbrave-150)
		Keytruda + Lenvima combo (KN-524) data at Asco 2020	Imfinzi + tremelimumab combo (Study 22) data at Asco 2020
2nd-line	Opdivo monotherapy approved Sep 2017 (CM-040)	Keytruda monotherapy approved Nov 2018 (KN-224)		–
	Opdivo + Yervoy combo approved Mar 2020 (CM-040)	Keytruda vs placebo failed confirmatory KN-240 study	–

https://www.evaluate.com/vantage/articles/events/conferences/asco-2020-after-tecentriqs-liver-win-spotlight-falls-merck-and

Fauci: Moderna Vaccine Data ‘Cautiously Optimistic,’ Expect Pfizer’s To Be Same

White House Coronavirus Task Force lead member Anthony Fauci in an interview with STAT on Monday said he was disappointed with the way Moderna Inc. MRNA 4.48% chose to publish data from phase 1 clinical trial of its novel coronavirus (COVID-19) vaccine.
“I didn’t like that,” the National Institute of Allergy and Infectious Diseases director told STAT.
Fauci said the vaccine maker should have waited to get the complete data from the first phase of the study and publish it in a “reputable journal.”
“But the company, when they looked at the data, as all companies do, they said, wow, this is exciting. Let’s put out a press release,” he added.
According to Fauci, the complete data is “quite similar” to the snippet Moderna published in the press release, and gives a reason to be “cautiously optimistic.”
“The initial data look very promising from the neutralizing antibody standpoint,” the NIAID director told STAT.
On other vaccines under development, Fauci said that Pfizer Inc.’s PFE 1.63% COVID-19 vaccine is very similar to that of Moderna’s candidate, and there’s no reason to believe that the results of its candidate will be any different.
“It’s an mRNA vaccine. I’m sure that Pfizer is going to get results that are as good as the Moderna vaccine,” he told STAT.
https://www.benzinga.com/news/20/06/16156922/fauci-reiterates-moderna-vaccine-data-is-cautiously-optimistic-expects-pfizers-results-to-be-the-sam

Inovio Analyst Watches Coronavirus Play ‘From The Sidelines’

Coronavirus vaccine play Inovio Pharmaceuticals Inc INO 5.15% is not an outright buy at this point in time, according to an analyst at Piper Sandler.

The Inovio Analyst

Christopher Raymond maintained a Neutral rating on Inovio shares with an $8 price target.

The Inovio Thesis

The 12-month overall survival data Inovio presented for its DNA cancer vaccine INO-5401 in glioblastoma multiforme — a deadly form of brain cancer — at the ASCO made the benefit less clear, Raymond said in a Monday note. (See his track record here.)
The vaccine is being studied in a Phase 2 single-arm study in newly diagnosed GBM patients following gross total resection and in combo with radiotherapy, temozolomide and Regeneron Pharmaceuticals Inc’s REGN 1.72% Libtayo, he said.
“While the data have demonstrated that a subset of patients had a T cell response to treatment, there is still uncertainty over INO-5401’s individual therapeutic benefit.”
Longer-term and randomized data for the vaccine would help Piper Sandler feel more confident in the program, Raymond said.
An overall survival update due later this year is a key catalyst for the program, the analyst said. Given the uncertainty, he said INO-5401 remains an unmodeled opportunity at this point.
Piper Sandler sees several upcoming catalysts for Inovio, including first-in-human data from INO-4800 due later this month and an update on potential funding for the program to support further development.
“However, given the ongoing volatility surrounding this name over COVID-19 efforts, we prefer to watch this story play out from the sidelines,” Raymond said.
https://www.benzinga.com/analyst-ratings/analyst-color/20/06/16159984/inovio-analyst-watches-coronavirus-play-from-the-sidelines

Commissioner Hahn Outlines Plans to Improve FDA Post-Pandemic

U.S. Food and Drug Administration (FDA) Commissioner Stephen M. Hahn recently gave a speech to the Alliance for a Stronger FDA. In it, he suggested that some of the changes forced on the agency by the COVID-19 pandemic are likely to become permanent.
Worth noting, as Hahn does, he took on the role of Commissioner of the FDA in December 2019, and was quickly thrust into an emergency footing because of the pandemic. Prior to taking on the role, he was chief medical executive at MD Anderson Cancer Center.
“I certainly did not anticipate a public health emergency of this magnitude when I joined the agency. And I could not have imagined how significantly my new role would change and be shaped by this pandemic. I definitely could not have known that discussions about personal protective equipment (or PPE) or face masks or nasal swabs would be central to my work as Commissioner.”
Part of the challenge, he notes, is to maintain the high standards of the agency while in the middle of a crisis. To that end, “I pledged to myself and emphasized to my new colleagues at FDA that our decisions would always be rooted in science.”
That being said, the U.S. response to the pandemic has been highly criticized. An April 20 op-ed in the New England Journal of Medicine by Benjamin N. Rome and Jerry Avorn, physicians from the Program Oon Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, note, “The global pandemic has put pressure on clinicians and the Food and Drug Administration (FDA) to act swiftly to make medications available to patients. When very limited observational and anecdotal evidence raised the possibility that the antimalarial drugs chloroquine and hydroxychloroquine may have activity against SARS-CoV-2, President Donald Trump quickly began celebrating the promise of their widespread use, stating on national television that he had a ‘hunch’ that such therapy was effective and that the drugs could be a ‘game changer’ in addressing the pandemic.”
Shortly afterwards, they point out, the FDA, “still facing criticism that its delays in approving testing kits for the virus hindered prevention efforts” issued an Emergency Use Authorization (EUA) on March 28 that allowed chloroquine and hydroxychloroquine for use in COVID-19, as well as their addition to the federal stockpile. “Its issuance,” they write, “was widely yet incorrectly reported by Trump and others as meaning that the FDA had approved the drugs for this indication. The Centers for Disease Control and Prevention (CDC) went so far as to publish doses of chloroquine and hydroxychloroquine for use in patients with COVID-19, though it later removed them from its website.”
Hahn listed his actions to date, including working to maintain the safety of the country’s food supply, monitoring for signs of foodborne illness outbreaks; facilitated efforts to development diagnostic tests, treatments and vaccines; “have helped facilitate increases in our national testing capacity, having helped ensure continued access to necessary medical products, and have sought to prevent the sale of fraudulent products.”
“To be sure,” he adds, “there were bumps along the road, but today we have an adequate supply of the devices that have been in unprecedented high demand such as PPE, ventilators, and others.”
Yet, today, USA Today published an article on clinical testing in the U.S., writing, “For nine critical weeks during the pandemic, the agency exercised little of its power to decide which companies could sell blood tests aimed at detecting whether someone was previously infected. In that vacuum of oversight, USA Today—in the most thorough independent review to date—found a nascent industry with inexperienced or dubious companies jockeying to cash in.”
The FDA has rebounded. USA Today wrote, “Facing withering criticism, the FDA recently tightened its restrictions, requiring companies to submit data on their test’s accuracy and how it will be marketed. In recent days, about 30 tests have been dropped from the FDA list, some of them voluntarily.”
The FDA responded to the USA Today findings in a written statement, saying that it takes fraud seriously and “continually monitors and conducts surveillance for fraudulent and inappropriately marketed medical products, including tests.”
Scott Becker, chief executive officer of the Association of Public Health Laboratories, told USA Today that lab representatives were on a March conference call with the FDA where the agency describes its initial plans to allow almost anyone to sell antibody tests, saying, “You could see the train wreck coming.”
Hahn’s rebuttal in his speech was, “As you have seen reported, early in the crisis we provided regulatory flexibility for developers with validated tests as outlined in our policies because public health needs dictated that we do as much testing as possible. But as the process has matured, we have helped increase the number of authorized tests, and we have adapted some of our policies to best serve the public need.”
But aside from some self-defense efforts, the focus of Hahn’s speed was on the need for the FDA to adjust to the pandemic and now it’s time to determine if some of those changes should be made permanent. “I have instructed my staff to identify the lessons learned from this pandemic and what adjustments may be needed, not just to manage this or future emergencies, but to make FDA itself more efficient in carrying out our regulatory responsibilities.”
Some of that involves streamlining some of the processes in developing new treatments, evaluating how clinical trials are designed and conducted, and the use of expanded access to meet the needs of patients not eligible or unable to participate in randomized clinical trials.
“Many of the permanent changes that we will implement really represent an acceleration of where we were headed before,” Hahn stated. “For example, the concept of decentralized clinical trials, in which trial procedures are conducted near the patient’s home and through use of local health care providers or local laboratories has been discussed before, and laid the foundation for some of the trials for COVID-19 products.”
He also emphasized the use of real-world evidence (RWE) in COVID-19 trials as something that is likely to stick post-pandemic. That was something that was being built in the later period of the previous commissioner, Scott Gottlieb’s leadership.
https://www.biospace.com/article/fda-s-hahn-commits-to-permanent-agency-change-post-covid-19/

Pfizer to invest up to $500 million in publicly owned drug developers

Pfizer Inc (PFE.N) said on Tuesday it will invest up to $500 million into publicly traded drug developers to fund their treatment candidates and provide access to the U.S. drugmaker’s scientific expertise.
Pfizer said it will make non-controlling investments in the biotechs with small- to medium-sized market capitalizations, but did not identify them.
The move comes at a time when the COVID-19 pandemic has led drugmakers to delay their clinical trials testing various therapies.
Pfizer said its Breakthrough Growth Initiative program, under which it was making the investment, allows partner companies to access its research, clinical development and manufacturing resources.
https://www.reuters.com/article/us-pfizer-investment/pfizer-to-invest-up-to-500-million-in-public-drug-developers-idUSKBN23922S

AAPS Sues the FDA to End Its Arbitrary Restrictions on Hydroxychloroquine

Today, June 2, 2020, the Association of American Physicians & Surgeons (AAPS) filed a lawsuit, AAPS v. FDA, against the Food and Drug Administration to end its arbitrary interference with the use of hydroxychloroquine (HCQ), which President Trump and other world leaders have taken as a prophylaxis against COVID-19.
Two million doses of HCQ are being sent by the Trump Administration to Brazil to help medical workers there safeguard themselves against the spread of the virus. But at the same time the FDA continues to block Americans’ access to this medication.
HCQ has been approved as safe by the FDA for 65 years, and the CDC states on its website that “CDC has no limits on the use of hydroxychloroquine for the prevention of malaria.”
More than 150 million doses have been donated to the strategic national stockpile controlled by the federal government, but unjustified FDA restrictions limit its use to only hospitalized patients for whom a clinical study is unavailable. Hospitals are even returning HCQ to the stockpile because they are not able to use it effectively.
“It is shocking that medical workers in Brazil will have access to HCQ as a prophylaxis while Americans are blocked by the FDA from accessing the same medication for the same use,” observes AAPS Executive Director Jane Orient, M.D.
“There is no legal or factual basis for the FDA to limit use of HCQ,” states AAPS General Counsel Andrew Schlafly. “The FDA’s restrictions on HCQ for Americans are completely indefensible in court.”
Many foreign nations, including China, India, South Korea, Costa Rica, United Arab Emirates, and Turkey, use HCQ for early treatment and prevention of COVID-19,  AAPS points out.
“Entrenched, politically biased officials at the FDA should not be allowed to interfere with Americans’ right to access medication donated to the federal government for public use,” Schlafly says. “By preventing Americans’ use of HCQ as a prophylaxis, the FDA is infringing on First Amendment rights to attend religious services or participate in political events such as political conventions, town halls, and rallies in an important election year.”
“FDA Commissioner Stephen Hahn states that the FDA does not interfere with physicians’ ability to prescribe HCQ, and yet at the same time the FDA denies access by millions of Americans to 150 million doses of it in the national stockpile,” Schlafly adds. “This irrational hoarding by government is an abuse of power.”
The Association of American Physicians and Surgeons (AAPS) has represented physicians of all specialties in all states since 1943. The AAPS motto is omnia pro aegroto, meaning everything for the patient.
PDF of complaint: http://aapsonline.org/judicial/aaps-v-fda-hcq-6-2-2020.pdf

AAPS Sues the FDA to End Its Arbitrary Restrictions on Hydroxychloroquine

Lonza sets new goal to make Moderna COVID-19 vaccine ingredients

Lonza aims to speed completion of two commercial production lines for Moderna Inc’s trial COVID-19 vaccine so manufacturing could start four to six weeks earlier than planned if the project is successful, the Swiss drugmaker’s chairman said on Tuesday.

Lonza, which hopes to make smaller batches of active ingredients for the U.S. biotechnology company’s experimental vaccine by July, now aims to finish a commercial production line in Portsmouth, New Hampshire, a month or so earlier than its original December 2020 target, Albert Baehny told Reuters.
A second commercial line, at Lonza’s site in Visp, Switzerland, had been slated for completion in January or February 2021 but now could be ready in December, he added.
Moderna, which enlisted Lonza in May in a 10-year manufacturing contract, is racing with 100-plus other vaccine projects, having last week dosed initial participants in a 600-patient study.

With accelerated deadlines, Lonza hopes to be ready to make vaccine ingredients quickly, should Moderna’s candidate pass muster with regulators.
“Four to six weeks would be remarkable, if we can gain this time,” Baehny, also Lonza’s interim CEO, said during a video interview. “We know the technology, we feel comfortable with the manufacturing steps. If we can accelerate, let’s do it. This is pandemic speed.”
He acknowledged potential bottlenecks, including hiring 60-70 employees to run each production line, availability of contractors and possible shortages of equipment like fermentation gear, could slow things down.
Lonza is financing the first $60-$70 million commercial production line in Visp, he said.

Moderna, flush with $483 million from the U.S. government and $1 billion-plus in fresh capital, is paying for the first U.S. production line, and up to three more at Lonza facilities in Portsmouth and Visp, Baehny said.
Combined capacity could produce ingredients for 600 million to 1 billion vaccine doses annually, he said, depending on the size of the dose needed.
https://www.reuters.com/article/us-health-coronavirus-vaccine-lonza-excl/exclusive-lonza-sets-new-goal-to-make-moderna-covid-19-vaccine-ingredients-idUSKBN2392C4