Six years after its formation Galvani Bioelectronics has treated its first patient. Galvani, a joint venture between Glaxosmithkline and Google’s sister company Verily Life Sciences, is developing a bioelectronic medicine – essentially applying neurostimulation to non-neurological disorders. Galvani has chosen rheumatoid arthritis as its first indication, and has started two small safety trials, one in the UK and another in the US, enrolling patients with moderate-to-severe RA who respond poorly to, or are intolerant of two or more biological or targeted antirheumatics. The technology comprises a neurostimulator implanted in the torso that sends impulses to the splenic nerve and the app-based software to control it. The theory is that the impulses alter immune cells in the spleen from a pro- to an anti-inflammatory state. Data from the US trial could come this year, and the company told the Financial Times that the device could be on the market in “four or five years”. It seems Galvani is some way behind Setpoint Medical, a group working to similar ends that also counts Glaxo among its investors. Setpoint’s vagus nerve stimulator began its pivotal US trial, also in RA, a year ago, with data expected towards the end of 2023.
Thursday, January 27, 2022
Scholar Rock’s quest for a better TGF-β drug
When it comes to biological targets with promise to improve the efficacy of PD-(L)1 blockade few have been hotter than TGF-β. And Scholar Rock, a group not primarily focused on oncology, is one of many biotechs ploughing the TGF-β furrow despite the failure of this approach’s most advanced candidate, Merck KGaA/Glaxosmithkline’s bintrafusp alfa.
Scholar has a two-pronged strategy to give it a better shot at success, its chief medical officer, Yung Chyung, tells Evaluate Vantage. It claims to have elucidated key aspects of TGF-β that have given its candidate, SRK-181, a broad therapeutic window, and at a scientific summit today revealed three key biomarkers that will inform SRK-181’s future trial design.
These biomarkers are cytotoxic (CD8+) T-cell infiltration into the tumour, phosphorylation of the protein Smad2, and the presence of myeloid-derived suppressor cells, Scholar Rock told today’s TGF-β Summit.
The second part of SRK-181’s phase 1 Dragon study is evaluating all these, with a view to a biomarker-driven strategy to assess and predict activity in trials. The findings are based on preclinical work suggesting that SRK-181 increases tumoural cytotoxic T cells, reduces P-Smad2, and reduces myeloid-derived suppressor cells; the company is working on assays to determine levels of these markers.
It is also important to stress that the potential of TGF-β blockade lies in combination with anti-PD-(L)1 MAbs. There is emerging evidence implicating TGF-β1 as a key driver of resistance by stopping immune system cells from penetrating into the tumour, says Mr Chyung, and SRK-181 could overcome resistance to anti-PD-(L)1 therapy.
Though Dragon initially tested SRK-181 monotherapy this was mainly to show safety with escalating doses. The study’s second part will investigate the anti-PD-(L)1 combo approach in tumours with primary resistance to PD-(L)1 blockade, effectively to show whether SRK-181 can turn such “cold” tumours “hot”.
Doing it wrong
This is something bintrafusp, a fusion protein combing TGF-β and PD-L1 blockade, did not show; even though bintrafusp remains in a few trials, its failures in NSCLC and cholangiocarcinoma resulted in Glaxo pulling the plug on a deal last September.
Mr Chyung reckons he knows where Merck KGaA went wrong, however. While not referring specifically to bintrafusp he says one problem with having both modalities in one molecule is limitation of dosing, in that the optimal dose for blocking PD-(L)1 is unlikely to be the same as that for blocking TGF-β1.
“Moreover, the molecule may be distributed locally within the tumour environment to areas where there is PD-1 or PD-L1 expression, which may not be the same sites where TGF-β1 is relevant, and vice versa,” he states.
A separate point that goes to SRK-181’s second supposed advantage is specificity. While bintrafusp and several other industry projects hit TGF-β SRK-181 has specificity for TGF-β1, a subtype that is “very challenging to drug. TGF-β comes as three different isoforms [that] are structurally quite similar, making it difficult to hit TGF-β1 without also hitting the others,” Mr Chyung explains.
The problem is that non-selective TGFβ blockade has potential for off-target toxicity. Scholar reckons it has achieved the desired specificity, allowing relatively high dosing, thanks to targeting the latent rather than the mature form of TGFβ1.
The competitor pipeline reveals just one other clinical asset with TGFβ1 subtype specificity, Pfizer’s PF-06952229, while Agenus and Jiangsu Hengrui are continuing with bispecifics. It is notable that Gilead abandoned Agenus’s AGEN1423, a bifunctional anti-CD73/TGFβ trap, over a year ago.
“It is important that SRK-181 is a MAb rather than a bispecific,” says Mr Chyung.
| Selected oncology assets targeting TGF-β | ||||
|---|---|---|---|---|
| Project | Company | Mechanism | Biomarkers? | Note |
| Phase 3 | ||||
| Bintrafusp alfa | Merck KGaA | Anti-PD-L1/TGF-β fusion protein | Triple-negative breast cancer trial specifies HMGA2 expression | Glaxosmithkline returned rights Sep 2021 |
| NIS793 | Novartis/Xoma | Anti-TGF-β MAb | No apparent biomarker enrichment | Earlier studied with spartalizumab, but ph3 is chemo combo |
| Retlirafusp alfa (SHR-1701) | Jiangsu Hengrui Medicine | Anti-PD-L1/TGF-β receptor 2 fusion protein | No apparent biomarker enrichment | China trials only |
| Phase 2 | ||||
| Vactosertib | Medpacto | TGF-β inhibitor | "Vactosertib responsive gene signature" identified | Keytruda and Imfinzi combos |
| Phase 1 | ||||
| AVID200 | Bristol Myers Squibb | Anti-TGF-β1&3 fusion protein | Seen to reduce Smad2 phosphorylation in ph1 | Acquired via Forbius takeover, Aug 2020 |
| SAR439459 | Sanofi | Anti-TGF-β MAb | Has shown CD8+ T-cell modulation in tumour microenvironment | Libtayo combo |
| PF-06952229 | Pfizer | TGF-β receptor 1 inhibitor | No apparent biomarker enrichment | Xtandi combo |
| ABBV-151 | Argenx/Abbvie | TGF-β-inactivating MAb | Study aims to identify biomarkers | Budigalimab combo |
| SRK-181 | Scholar Rock | Anti-TGF-β1 MAb | CD8+ T-cell infiltration, phosphorylated Smad2 & MDSCs identified | Combo with approved anti-PD-(L)1 drug |
| AGEN1423 | Agenus | Anti-CD73-TGFβ bifunctional MAb | None evident; ph1 study terminated | Gilead returned rights Nov 2020 |
| Source: Evaluate Pharma, clinicaltrials.gov & academic journals. https://www.evaluate.com/vantage/articles/news/trial-results/scholar-rocks-quest-better-tgf-b-drug | ||||
Vaccine mandate for health workers starts to take effect
Health workers in about half of the United States Thursday will need to be vaccinated against COVID-19 as the Biden administration's requirement takes effect.
Enforcement of the requirement begins in 25 states and the District of Columbia, and will extend to every other state except Texas on Feb. 14. Enforcement in Texas will start Feb 22.
The Centers for Medicare and Medicaid Services staggered the deadlines because of various lawsuits brought by GOP-led states. Subsequent court rulings blocked the requirement in some states but not others, leading to a patchwork of different rules before the Supreme Court earlier this month allowed the requirement to take effect.
Thursday's deadline requires staff at all facilities and providers certified under Medicare and Medicaid to have received at least the first dose of a primary series or a single dose COVID-19 vaccine prior to providing any care, treatment or other services.
Employees will have another month to receive their second doses, if required.
The court ruled 5-4 to keep the health care worker mandate, with Chief Justice John Roberts and Justice Brett Kavanaugh joining the more liberal Justices Stephen Breyer, Sonia Sotomayor and Elena Kagan.
The order will cover about 10.3 million health workers across every section of the health industry, including doctors, nurses, technicians and even volunteers at every facility that participates in Medicare or Medicaid.
It provides for narrow exemptions on religious and medical grounds.
Employees can be fired for not complying, and if the noncompliance is facility-wide, it could result in termination from the Medicare and Medicaid programs.
Health experts say there’s clear evidence that mandates work in getting more people vaccinated. As the omicron variant rips through the country, infecting both vaccinated and unvaccinated health workers, there's a sense of urgency in making sure essential health workers are protected from serious disease or death.
But hospitals and nursing homes have expressed concern that the requirements could result in staffing shortages, especially in states that haven't had any mandates or where governors have banned them.
Just ahead of Thursday's deadline, Montana's Sen. Steve Daines (R), Rep. Matt Rosendale (R) and Gov. Greg Gianforte (R) sent a letter to the Biden administration asking for the vaccine requirement to be waived in the state's rural health facilities.
"We are deeply concerned that the vaccine mandate will penalize healthcare entities that simply cannot comply with the mandate due to ongoing workforce challenges," they wrote. "Some Montana facilities cannot afford to lose another healthcare professional, especially when alternative measures can be implemented, such as masking and testing, to protect the safety and health of employees, patients, and visitors from COVID-19."
Fed watchdog faults HHS leaders for sustained public health crisis failures
The Department of Health and Human Services has failed to correct longstanding issues related to its ability to respond to public health emergencies, according to a nonpartisan government watchdog report.
The Government Accountability Office on Thursday added HHS to its "High Risk List" of federal departments and programs susceptible to waste, fraud and abuse without significant changes
"For over a decade, we have found issues with how HHS's leadership prepares for and responds to emergencies, including COVID-19, other infectious diseases, and extreme weather events, such as hurricanes," GAO wrote in the report.
"If left unaddressed, these deficiencies will continue to hamper the nation’s ability to be prepared for, and effectively respond to, future threats. As devastating as the COVID-19 pandemic has been, more frequent extreme weather events, new viruses, and bad actors who threaten to cause intentional harm loom, making the deficiencies we have identified particularly concerning," the report added.
The deficiencies include failure to establish clear roles and responsibilities for other partners involved in the pandemic or disaster response; issues collecting and analyzing data to inform decisionmaking; difficulties providing clear and consistent communication to key partners and the public; and problems establishing transparency and accountability to help ensure program integrity and build public trust.
Specifically, the report faulted HHS for working with the Federal Emergency Management Agency to develop plans to mitigate supply chain shortages for the remainder of the pandemic.
GAO also criticized the agency because it has yet to develop a comprehensive and publicly available testing strategy, which GAO recommended it do in January 2021.
In total, GAO said it gave the agency 115 different recommendations since fiscal year 2007; 72 of those remain open.
The GAO report is part of a series of congressionally mandated evaluations of the government's pandemic response.
It comes as two leading bipartisan senators this week released draft legislation that would overhaul how HHS responds to future pandemics and establish a 9/11 Commission-style investigation into the COVID-19 response.
The measure from Sens. Patty Murray (D-Wash.) and Richard Burr (R-N.C.) would not directly provide new funding for pandemic preparedness, though it would authorize some programs that could be funded as part of the annual appropriations process.
It would also make the CDC director a Senate-confirmed position and require the agency to develop a strategic plan every four years.
GAO said it recognizes that "numerous public health emergencies converging and occurring simultaneously can present significant challenges and tax already strained resources."
However, the report concluded, "waiting to address the deficiencies we have identified in HHS’s leadership and coordination of public health emergencies is not an option as it is not possible to know precisely when the next threat will occur; only that it will come."
Battling COVID with one hand tied behind our back
Two years after the first confirmed case of COVID-19 in the U.S., hope is on the horizon in the form of recently authorized antivirals that may protect high-risk COVID patients from severe illness.
Leave it to the federal government to get in the way.
Health officials could make the antivirals more easily accessible to Americans by granting pharmacists the authority to prescribe and dispense them. Unfortunately, federal authorities’ failure to remove bureaucratic obstacles and cut red tape is making it much harder for patients to obtain these potentially life-saving treatments.
The Food and Drug Administration (FDA) opened the door for these new, promising treatments by issuing a pair of emergency-use authorizations (EUA) last month for Pfizer’s Paxlovid as well as Merck and Ridgeback’s Molnupiravir. Both were authorized for high-risk COVID patients — Paxlovid for people over the age of 12 and Molnupiravir for patients over the age of 18 who are not pregnant. Both treatments are oral, and both are most effective when taken within five days of the onset of symptoms.
Both antivirals show significant promise — Paxlovid may reduce hospitalization and death by 88 percent, and Molnupiravir by 30 percent. But ultimately, these numbers will only matter to patients who can access these treatments — when they need them.
Under the EUA, the FDA may evaluate the totality of the scientific evidence, as well as the treatments’ known risks and potential benefits. If the agency determines either treatment may be effective, it can be approved under EUA while the public health emergency remains in effect.
In order to access the treatment, patients must first obtain a COVID test, which can be difficult in some hard-hit areas, then get the approval of a physician (or other medical provider, usually in a physician’s office or the like), and then make their way to the pharmacy to fill the prescription. But remember: The treatment is most effective within the first five days of symptom onset, which means high-risk patients face a complicated race against the clock.
One of the success stories of the pandemic has been the ability of health care providers, including pharmacists, to practice at the top of their education and training. Pharmacies are not only convenient, but they enjoy an enormous amount of trust from their communities, and they have been indispensable in the fight against COVID-19. The federal government granted pharmacies the authority to provide immunizations, and they have since administered more than 215 million doses, not to mention an untold number of COVID tests.
Yet, the FDA stopped short of giving them similar authority when it comes to these two antivirals.
The FDA has the power to authorize pharmacists to prescribe and dispense these antivirals — but it didn’t. While the agency provided no public reason, some suspect the decision was made over concern of potential drug interactions. But pharmacists are often the very providers who have the best insight into a patient’s drug history. They also have previous authorization to prescribe and dispense oral therapeutics under the Public Readiness and Emergency Preparedness (PREP) Act, but the FDA chose to rescind that authority without explanation.
And since the previously authorized IV treatment of monoclonal antibodies seem to be ineffective against the current, dominant omicron variant, the Biden administration has now halted shipments of this treatment to the states. Even though the two, recently authorized antiviral pills are currently facing supply shortages, the federal government should make every effort to ease access to the best, currently available treatments.
Failing to grant pharmacists the same extension of prescribing authority for these antiviral pills that were granted for the COVID vaccines is another giant misstep. And it’s a reminder that the same federal government that seeks to impose restrictions and rules also bears some responsibility for delaying this important treatment to some of the patients who need it most. It turns what could have been a one-stop shop into a complicated, time-wasting and meaningless chase for the patients most vulnerable to COVID-19.
Naomi Lopez is the director of health care policy at the Goldwater Institute.
https://thehill.com/opinion/healthcare/591620-battling-covid-with-one-hand-tied-behind-our-back
FDA Asks Court To Delay First 55K Batch Of COVID Docs; Pfizer Moves To Join Case
by attorney Aaron Siri via Injecting Freedom (emphasis ours),
As explained in prior posts, in a lawsuit seeking all of the documents the FDA relied upon to license Pfizer’s COVID-19 vaccine, a federal judge shot down the FDA’s requested rate of 500 pages per month and instead ordered the FDA to produce at the rate of 55,000 pages per month starting on March 1.
Since the government has trillions of dollars of our money, it is putting it to good use by fighting to assure that the public has the least amount of transparency possible. To that end, it has now asked the Court to make the public wait until May for it to start producing 55,000 pages per month and, even then, claims it may not be able to meet this rate.
The FDA’s excuse? As explained in the brief opposing the FDA’s request, the FDA’s defense effectively amounts to claiming that the 11 document reviewers it has already assigned and the 17 additional reviewers being onboarded are only capable of reading at the speed of preschoolers.
Meanwhile…
As the FDA tries to obtain months of delay, guess who just showed upon in the lawsuit? Yep, Pfizer. And it is represented by a global chair and team from a law firm with thousands of lawyers. Pfizer’s legal bill will likely be multiple times what it would cost the FDA to simply hire a private document review company to review, redact, and produce the documents at issue. Within weeks, if not days.
Pfizer is coming in as a third party. But Pfizer assures the Court it is here to help expedite production of the documents. Sure it is! Where was Pfizer before the Court ordered the 55,000 pages per month? Right, doing what it normally does: letting the government work on its behalf – like the way the government mandates, promotes, and defends Pfizer’s product.
But the government did not please Pfizer this time and so here it comes, likely looking for a second bite at the apple. Of course the FDA consented to Pfizer appearing. You can read the response my firm filed to Pfizer’s motion , as well as all of the other relevant recent filings in the link provided below.
Let me end by noting that all of this insanity is simply in response to an attempt to obtain some basic transparency. This should again bring into sharp focus why the government should never coerce or mandate anyone to get an unwanted medical product or procedure. Just look at this circus – the government mandates Pfizer’s product, gives it immunity for any safety or efficacy issues, promotes its product using taxpayer money, gives Pfizer over $17 billion and then uses taxpayers’ money to fight to avoid providing even the most basic level of transparency to the public.
The introduction from the brief opposing the FDA’s request is below and you can find copies of all the relevant court filings (FDA Motion to Modify Scheduling Order, January 18, 2022 / Plaintiff Opposition to Motion to Modify, January 24, 2022 / Pfizer Motion to Intervene, January 21, 2022 / FDA Response to Pfizer Motion, January 25, 2022 / Plaintiff Response to Pfizer Motion, January 25, 2022) here:
INTRODUCTION TO OPPOSITION TO FDA’S MOTION
It is understandable that the FDA does not want independent scientists to review the documents it relied upon to license Pfizer’s vaccine given that it is not as effective as the FDA originally claimed, does not prevent transmission, does not prevent against certain emerging variants, can cause serious heart inflammation in younger individuals, and has numerous other undisputed safety issues.[1] However, the FDA’s potential embarrassment over its decision to license this product must take a back seat to the transparency demanded by FOIA and the urgent need and interests of the American people to review that licensure data. The Court already recognized this unprecedented urgent need in its January 6th order directing the FDA to produce 55,000 pages per month.
The FDA now insists it must delay its first 55,000-page production until May 1, 2022 – four months after the Court entered its order. However, the FDA’s own papers seeking this delay make plain it can produce at a rate of 55,000 pages per month in February and March. The FDA affirms it has already “allocated the equivalent of nearly 11 full-time staff to this project” and that “a review speed of 50 documents per hour was within the normal range for document review in a complex matter” in private practice; and here the 50 document per hour rate would be faster since there is only a need to review for personally identifying information (“PII”) for most pages. Hence, if the FDA’s 11 full-time reviewers work only 7.5 hours per day and review 50 pages (not documents) per hour, the FDA could review over 88,000 pages per month in February and March. That is more than sufficient to produce the 55,000 pages per month currently ordered for these two months.
Instead of complying with this Court’s reasoned order, the FDA claims these 11 reviewers can only review a total of 10,000 pages per month. What the FDA does not say, and what basic math shows, is that a rate of 10,000 pages a month for 11 full-time reviewers amounts to only 5 pages per hour! This rate is made even more absurd because most of the pages the FDA will be reviewing during this period are repetitive data files that only require second level review to redact minimal amounts of PII that Pfizer may have left in the documents. FDA’s reality defying claim and contemptuous approach to its production obligations should not be countenanced. (Infra § I.)
It is also apparent that the instant demand is just the start of a campaign to delay the production ordered by the Court. In this first salvo, the FDA is not really asking the Court. It is instead expressly telling the Court it does not intend to produce more than 10,000 pages per month for February and March, and despite claiming it is making “unprecedented” efforts, the FDA repeatedly tells the Court: “It is not possible to guarantee that FDA will be able to fully comply” with the 55,000-page production rate thereafter. (Dkt. No. 38 at APPX004, APPX008.) Americans must follow the law and the FDA, a multi-billion-dollar agency, should similarly be given no safe harbor from complying with the orders of this Court. (Infra § II.)
The FDA should also be held to what it attests. The FDA, with over 18,000 employees and an over $3 billion discretionary budget, repeatedly assures the Court that it is taking steps to “marshal every possible resource available to it,” “acting with maximal urgency to assemble every possible resource available to it” and “putting every available resource at its disposal into its efforts to achieve compliance.” (Dkt. No. 37 at 10, 3, 10.) The FDA also attests that over the coming weeks, it will have 28.5 full-time people reviewing the documents. Working 7.5 hours per day for 20 business days per month, 28.5 people reviewing 50 pages per hour can review a total of approximately 213,750 pages per month. Putting aside that most of this production can be reviewed far faster than the rate of 50 pages per hour, Plaintiff asks that the FDA be held to its representations and be directed to produce at the rate of 180,000 pages per month starting in April. (Infra § III.)
The Court is, other than Congress, the only check on the FDA. In a free country, transparency is paramount, and the FDA has chosen to thwart transparency and the requirements of FOIA by anemically understaffing the office it maintains to respond to FOIA requests. It is akin to the boy that kills his parents and asks for sympathy for being an orphan. Decrying that this Court is now making it comply with the law – by actually producing documents in a timely manner – is ridiculous. It is also incredible for the FDA to claim that compliance here would harm its health policy objectives. Even if the FDA really does need to spend $4 to $5 million which, as shown below, is an absurd overestimate, that is an inconsequential amount of its overall $3.41 billion discretionary budget. Moreover, the issues with the Pfizer vaccine – including waning immunity, variants evading immunity, the failure to prevent transmission, myocarditis, and pericarditis – show that the FDA’s priority should be to address this product before rushing off to engage in other activities. (Infra § IV.)
For these reasons, as explained below, the Court should refuse to reduce the rate of production in February and March and should increase the rate of production for April and thereafter to 180,000 pages per month consistent with the FDA employing 28.5 full-time reviewers in the coming weeks to conduct the review and the fact that most of the pages need only be reviewed for PII.
…you can read the rest of the brief here
[1] Reflecting the issues with this product, the FDA failed to send a representative to a federal court hearing in this matter on December 14th because of the “FDA’s protocols” regarding COVID-19. Meaning, despite the FDA’s claim the vaccine is “effective,” the FDA is apparently still scared to send a representative to the hearing. Its actions speak volumes and cast serious doubt on its words.
Trump’s Operation Warp Speed ‘very helpful’ for COVID vaccine development: author
Former president Donald Trump in recent weeks has intensified his public support for COVID-19 vaccines, revealing that he received a booster shot and denouncing politicians who withhold their booster status as "gutless."
The flurry of remarks comes as some public health experts have called for a second version of the Trump administration's vaccine development program, Operation Warp Speed, in response to the emergence of variants like Omicron
But the push for a new iteration of the vaccine program rekindles debate about the successes and failures of the first initiative.
In a new interview, Gregory Zuckerman — an investigative reporter at the Wall Street Journal and author of "A Shot to Save the World: The Inside Story of the Life-or-Death Race for a COVID-19 Vaccine" — says Operation Warp Speed was "very helpful" to U.S. vaccine development, despite some missteps.
"Like most every other topic in society today, it's sort of black and white," Zuckerman told Yahoo Finance on Nov. 15, before the detection of the Omicron variant. "Either Operation Warp Speed saves everything, and we have to give Donald Trump all the credit, or it was useless."
"I come down somewhere in the middle, meaning that Operation Warp Speed was very helpful," he adds. "There was a lot of money that was given to these companies [and] resources too, little parts that were necessary from all over the country that were brought to the necessary spots.”
Launched in April 2020, Operation Warp Speed drew on $14 billion in federal investment to foster public-private partnerships with pharmaceutical companies.
While Pfizer (PFE) declined government funding for research, it later sold its vaccine to the U.S. for $2 billion. On the other hand, Moderna (MRNA) accepted a total of $4.1 billion in public investment for research and development as well as the acquisition of 200 million doses.
The program helped the U.S. develop a vaccine over a short timespan of 10 months, far less than the 10 years it took to develop a measles vaccine or the 16 years it took to achieve a Hepatitis B vaccine, McKinsey & Company noted in a report last March.
But Operation Warp Speed wasn't perfect. The program spent $1.2 billion on the purchase of 300 million doses of the vaccine developed by AstraZeneca and Oxford University. U.S. health authorities still have not approved that vaccine.
Despite the ultimate success of the Moderna vaccine, Operation Warp Speed focused its early investment and attention on the AstraZeneca candidate, Zuckerman said.
"You have to remember that Warp Speed made an early bet on a different vaccine, the AstraZeneca vaccine," Zuckerman says. "It did not give money to Moderna early on when it was desperate for money."
To be sure, Trump has opposed some vaccine-related policies — especially mandates. Earlier this month, he urged supporters to "rise up" against possible vaccine mandates for young children, Business Insider reported.
All three Supreme Court justices appointed by Trump joined the majority earlier this month in rejecting the Biden administration's vaccine-or-test rule for businesses with more than 100 employees.
Speaking to Yahoo Finance, Zuckerman noted that Operation Warp Speed contributed to U.S. vaccine development but doesn't account entirely for its success.
"Warp Speed was very helpful," he says. "But you don't want to say it was all due to Warp Speed — the success of these remarkable vaccines."