After scraping through a tough advisory committee in March, the FDA has returned a verdict for Provention Bio’s Type 1 diabetes medicine: It’s a no.
Specifically, the FDA has slapped a complete response letter on Provention for teplizumab, which was gunning for an approval to help delay clinical Type 1 diabetes in at-risk individuals.
In the trial that underpinned the drug’s application, Provention said teplizumab delayed the onset of Type 1 diabetes by a median of two years. That delay could help patients avoid diabetic ketoacidosis, a life-threatening complication of diabetes.
Back in March, FDA experts assessing the drug raised concerns about how small the study was—it didn’t meet its enrollment goal and wound up testing teplizumab in just 44 patients—and about the fact that the study did not follow patients after their diabetes diagnosis.
The company also submitted safety data from other trials of the drug in another indication, which the FDA reviewers noted were not a perfect comparison.
Now, the FDA is sharing its own concers, many of which were predicted. In a release from the biotech (the FDA doesn’t publicize complete response letters itself), the FDA stated that a single, low-dose pharmacokinetic/pharmacodynamic (PK/PD) bridging study in healthy volunteers to compare planned commercial product with drug product originating from drug substance manufactured for historic clinical trials “had failed to show PK comparability.”
“As PK remains the primary endpoint for demonstration of comparability between the two products, you will need to establish PK comparability appropriately between the intended commercial product and the clinical trial product or provide other data that adequately justify why PK comparability is not necessary,” the FDA said, as quoted by Provention.
The FDA is also asking for a “safety update” as part of its BLA resubmission, though Provention gave no specifics here.
The biotech said it expects “relevant additional” PK/PD data out from a PK/PD sub-study in patients receiving 12 days of therapy in the ongoing phase 3 Protect trial in newly diagnosed Type 1 diabetes patients “later this quarter.”
These data “will determine whether to submit these data to the FDA for its review,” Provention said, “to support PK comparability or otherwise justify why PK comparability is not necessary.”
And it doesn’t end there: There were also some manufacturing issues. The FDA uncovered “certain deficiencies” amid a recent general inspection at a fill/finish manufacturing facility, and, though not specific to teplizumab, this will need “to be resolved before approval.”
“The CRL contained other comments and recommendations that do not impact approvability, as well as general guidance regarding the resubmission process,” but again gave no details about these.
We do know that this will cause delay and likely more expense, and further knocks back the biotech, which had been flying high ahead of its advisory committee though was brought back to Earth by its squeezing past.
The company had been bullish that it could bypass some of these issues, but clearly, the FDA had other ideas.
“We want to recognize the patients, their families, study investigators, clinicians and T1D champions that have played such a crucial role in the development of teplizumab and thank our partners and our team of dedicated employees and consultants for their outstanding contributions,” said Ashleigh Palmer, co-founder and CEO of Provention Bio.
“We also want to acknowledge the efforts of Drs. Yanoff and Unger and the review team at the FDA, who have worked so closely and transparently with us throughout the priority review of our BLA for this Breakthrough Therapy drug.
“We know the T1D community is urgently awaiting therapeutic advancements to address their medical needs and believe our collective passion and commitment will continue to drive us forward to meet this goal. We will continue to work collaboratively with the FDA to hopefully secure approval of teplizumab and bring the first disease-modifying therapy for T1D to at-risk patients as soon as possible.”
Innate Pharma SA said Tuesday that it would no longer explore its drug avdoralimab in Covid-19 after missing its Phase 2 targets but would continue to investigate its use in inflammation.
The oncology-focused biotech company said it didn't meet its primary endpoints in all three of its trial cohorts of Covid-19 patients with severe pneumonia.
The company said preclinical data that were observed didn't translate into clinical benefit over best supportive care.
Innate Pharma said these results don't affect the investigator-sponsored, Phase 2 trial of the treatment in the inflammatory disease bullous pemphigoid, for which it is enrolling patients.
Chinese pharmaceutical shares skidded Tuesday as new draft rules for conducting oncology drug trials could increase research and development costs, analysts said.
Shanghai Fosun Pharmaceutical (Group) Co.'s A-shares shed 9.6%, while Hangzhou Tigermed Consulting Co. fell 11% and WuXi AppTec Co. declined 5.1%. The companies' Hong Kong-listed shares lost between 4.7%-8.6%.
A draft of the policy, released Friday by China's Center for Drug Evaluation, takes aim at "the low quality and repetitive R&D" of drugs developed in China, and seeks to push pharmaceutical companies to focus on innovation, said Daiwa Capital Markets analyst Dennis Ip.
Tigermed, which provides clinical research services for pharmaceutical product development, might be hit relatively hard in the short term, given its heavy reliance on Chinese clients for revenue, Mr. Ip said. Other companies like WuXi AppTec and Wuxi Biologics (Cayman) Inc. will be less affected since their largest revenue sources are from international clients, he added.
Changes in regulation will likely have limited impact on drugs that are already in the clinical-trial stage, given that the draft rules are still in the consultation stage, Soochow Securities said. The brokerage said higher requirements for conducting clinical trials should benefit drugmakers with greater capital resources and experience in clinical-trial designs.
Scientists have designed a temporary, battery-free pacemaker that can be broken down by the patient’s body when its work is done, the latest advance in the emerging field of bioelectronics.
In a paper published this week in Nature Biotechnology, researchers report that the device reliably kept the heart’s pace in check in tests on mice, rats, and other animals, as well as in human heart tissue in a dish. And while the research is still in the early stages, the scientists say the pacemaker was able to overcome key limitations of existing devices.
“There are about 1 million people a year who receive pacemaker implantations worldwide. It’s a huge, huge medical field, but mostly pacemakers are permanent,” said Igor Efimov, a biomedical engineer and professor at George Washington University and co-author of the new paper.
Unlike traditional pacemakers, which are left inside a patient for the rest of their life or until the battery dies, a traditional temporary pacemaker is implanted and later removed. The devices are typically for children with congenital heart defects or adults who have had a coronary artery bypass graft, who may need a temporary pacemaker to correct a slowed heart rhythm for only a few days or weeks.
A traditional temporary pacemaker has wires connected to the heart, which poke out of the skin and attach to external hardware. Some experts say that setup could raise the risk of infection, potentially injure the heart when the lead is removed, and can hamper patient mobility. Being able to move around after surgery is especially valuable as patients recover.
“The patient will be more free to move around after the surgery,” said Moussa Mansour, director of the Atrial Fibrillation Program at Massachusetts General Hospital. Mansour, who was not involved in the research, added that “the more you keep the patient in bed, the more likely they are to develop clots in their legs or pneumonia” or other complications.
The new device overcomes some of those challenges with the help of an external coil that can be sewn into a patient’s shirt or placed as a patch on the patient’s chest, where it transmits energy to power the pacemaker.
“You know when you try to charge a phone wirelessly? It’s exactly the same principle,” said Efimov.
Because all of the complex programming for the pacemaker is done not in the device itself, but in external hardware, it isn’t confined by circuits that would otherwise be needed to communicate and process heart information. That means the device can be tiny and thin — less than a millimeter thick — which makes it easier to implant.
“It’s restricted just by the size of the antenna, which will harness the energy,” said Efimov.
Efimov and his colleagues were able to build on past research into bioresorbable materials, which have been developed and used for other applications for years. They selected materials that could be slowly and safely absorbed by the body. The thickness or type of materials used can change depending on how long the temporary pacemaker needs to last. The materials — some organic, silicone-based, or metals like magnesium — are also relatively affordable and comparable to the costs of a typical pacemaker, according to Efimov. The primary cost for manufacturing the devices would come from the external hardware the device requires.
Mansour said that while such a device would not necessarily increase the life span of a patient beyond what current pacemakers accomplish, it could improve patient quality of life.
“It seems to be a very revolutionary idea. I believe it’s going to be well-received in the field. It targets an unmet need, and I believe it’s going to benefit patients,” said Mansour.
The device could be beneficial for hospitals, Mansour said, given that patients who require a temporary pacemaker are typically roomed in the intensive care unit — valuable real estate in a hospital setting. Because patients with this new device wouldn’t be fixed to a single spot, the ICU could be reserved for patients who need the space more.
He also sees value in the research beyond its initial target. A biodegradable platform could be useful in treating a number of other conditions.
“That’s where the strength of this technology is,” Mansour said, “not only because it targets a temporary patient application, but because of its potential to be expanded to other applications in medicine.”
Japan said on Tuesday it would ship millions more doses of AstraZeneca Plc's COVID-19 vaccine to Asian neighbours this week as a continuation of bilateral donations.
Japan will send 1.13 million more doses to Taiwan on Thursday, Foreign Minister Toshimitsu Motegi told reporters at a regular press conference, after previously delivering 1.24 million doses last month.
A further 1 million doses each will be sent to Thailand, the Philippines, and Vietnam this week, following earlier donations to Indonesia and Malaysia, Motegi said.
"True friends always lend a hand when they need each other the most," Taiwanese Premier Su Tseng-chang wrote on his Facebook page.
In further good news for Taiwan's vaccine programme, Health Minister Chen Shih-chung told reporters in Taipei that 620,000 additional AstraZeneca doses would arrive on Wednesday, part of the government's direct order from the company.
Japan has arranged to buy 120 million doses of AstraZeneca's vaccine, with most of that supply produced by domestic companies. Regulators approved the shot in May, but amid lingering concerns about blood clots, health authorities have relied on the mRNA-type vaccines made by Pfizer Inc and Moderna Inc in Japan's inoculation push.
Japan has pledged $1 billion and 30 million doses to the global vaccine sharing scheme COVAX, but so far its donations have been outside of that programme.
AstraZeneca doses produced in Japan have not yet been approved by the World Health Organisation for use in COVAX, Motegi said, so the country has turned to bilateral deals to respond to "urgent requests for vaccine supplies."
Japan's first shipments through the COVAX facility are expected in the middle of this month, with some 11 million doses bound for nations in south Asia and the Pacific islands, Motegi said.
Israel reported on Monday a decrease in the effectiveness of the Pfizer/BioNTech COVID-19 vaccine in preventing infections and symptomatic illness but said it remained highly effective in preventing serious illness.
The decline coincided with the spread of the Delta variant and the end of social distancing restrictions in Israel.
Vaccine effectiveness in preventing both infection and symptomatic disease fell to 64% since June 6, the Health Ministry said. At the same time, the vaccine was 93% effective in preventing hospitalizations and serious illness from the coronavirus.
The ministry in its statement did not say what the previous level was or provide any further details. However ministry officials published a report in May that two doses of Pfizer’s vaccine provided more than 95% protection against infection, hospitalization and severe illness.
A Pfizer spokesperson declined to comment on the data from Israel, but cited other research showing that antibodies elicited by the vaccine were still able to neutralize all tested variants, including Delta, albeit at reduced strength.
About 60% of Israel’s 9.3 million population have received at least one shot of Pfizer’s vaccine in a campaign that saw daily cases drop from more than 10,000 in January to single digits last month.
This spurred Israel to drop nearly all social distancing as well as the requirement to wear masks, though the latter was partially reimposed in recent days. At the same time, Delta, which has become a globally dominant variant of the coronavirus, began to spread.
Since then daily cases have gradually risen, reaching 343 on Sunday. The number of seriously ill rose to 35 from 21.
Data scientist Eran Segal of Israel’s Weizmann Institute of Science said the country was unlikely to experience the high levels of hospitalizations seen earlier in the year since there were much fewer critically ill.
He said it was fine to “continue with life back to normal and without restrictions” while stepping up measures like vaccination outreach and ensuring testing for Israelis returning home from abroad.
Last week, the CDC's Advisory Committee on Immunization Practices (ACIP) met to discuss the safety signal of myocarditis among young people who receive mRNA vaccination against COVID-19. This dialogue has been months in the making. Ultimately, the panel continued to endorse a two-dose mRNA strategy for all ages. We are concerned with this recommendation and offer five alternative considerations. But first, let's review how we got to this moment in order to make sense of vaccine-induced myocarditis.
A Recent History of Vaccine-Induced Myocarditis
The potential risk for vaccine-induced myocarditis was first raised on February 1 in the Jerusalem Post, which reported the hospitalization and intensive-care admission of a healthy 19-year old male 5 days after receiving his second dose of the Pfizer vaccine. This was followed by a nationwide report in the Times of Israel on April 23, later picked up by Reuters on April 25. These news reports suggested that Israel had seen elevated rates of this event after young men were vaccinated with the Pfizer vaccine, almost always after the second dose (56 out of 62 cases or 90%).
The European Medicines Agency announced an investigation on May 7, which was the same day several of us cautioned against FDA's use of emergency use authorization (EUA) to expedite the availability of COVID-19 vaccines to U.S. kids ages 12 to 15.
Although they were aware of this safety signal, the FDA issued the EUA on May 10 for Pfizer's mRNA vaccine in kids ages 12 to 15. Despite the fact that the vaccine was already widely in use in people ages 16 and above under the existing EUA, specific rates of myocarditis in the U.S. for 'near age' vaccine recipients (kids ages 16 to 18) were not made publicly available. In other words, no data on myocarditis events in kids close in age to the group receiving the new EUA (those ages 12 to 15) were leveraged in the process for granting this EUA. This is unfortunate, as these data would have had the greatest relevance and implications for the adjacent-age group.
Over the last 2 months, several news reports on clusters of cases of myocarditis after mRNA vaccination -- particularly in young men -- have been reported in the U.S. Revised estimates from Israel found the rate of myocarditis to be to one in 3,000 to one in 6,000 among males ages 16 to 24. On May 26, the Times of Israel reported that Israel's health ministry would consider just one dose in teens to balance getting most of the benefit of viral protection against mitigating much of the risk of myocarditis.
On May 22, the CDC announced they had received reports of myocarditis, and asked healthcare providers to file additional and missing reports into the Vaccine Adverse Event Reporting System (VAERS).
Last week, on June 23, ACIP met to discuss the findings. To date, CDC has documented myocarditis in at least 323 cases age 29 or under (of whom 96% were hospitalized), while 148 remain under review. The CDC acknowledged more cases in young people than older people, more cases in young males than young females, and higher incidence after dose two than dose one. The absolute risk of myocarditis after the second dose based on the number of CDC confirmed cases would be one in 15,000 to 20,000 for boys ages 12 to 24. There is a smaller but still excess risk in women age 24 and younger.
At its meeting, ACIP considered figures and data, which claimed to weigh the benefits versus harms of "dose two" of mRNA vaccines in this age group. However, in reality, the scenarios presented by the CDC compared the risks versus benefits to young people of no vaccination at all versus a scenario in which they received both shots.
The CDC did not consider the harms versus benefits of one versus two doses, but only the harms versus benefits of vaccination itself. But the CDC went beyond this. They also used base rates of infection from the past, rather than current rates of SARS-CoV-2 spread, which are substantially lower. They did not differentiate between healthy kids -- who are at risk of idiosyncratic events, such as myocarditis -- and kids with pre-existing medical conditions that place them at high risk of severe outcomes from COVID-19, including hospitalization.
This insistence on an all-or-nothing, one-size-fits-all binary approach -- treating healthy kids who have recovered from confirmed prior infection as equivalent to infection-naive kids with comorbidities -- is at the heart of the fallacy underpinning ACIP's decision.
While we acknowledge the CDC and ACIP had to act based on short-term studies and limited and variable data, vaccines must be used in a way that maximizes benefit and minimizes risk.
Ultimately, the CDC's recommendations came out so unequivocally in favor of vaccination that the following is true: If a 15-year-old recovers from COVID-19 and has high antibody levels, and this 15-year-old then receives one dose of mRNA vaccine causing hospitalization from myocarditis, the CDC would still contemplate proceeding with dose two once the "heart has recovered."
These events raise several points of concern:
VAERS is a suboptimal system. While the VAERS system was well-positioned to detect a rare and entirely unprecedented safety event (e.g., vaccine induced thrombocytopenia and thrombosis in the cerebral vessels), the system is suboptimal for elevations in naturally occurring health outcomes. Voluntary reporting requires a provider to make a mental link between vaccination and the outcome, and the mere fact that the CDC received more cases after coverage in the New York Times is evidence that VAERS failed to capture these events without prompting. This indicates cases may still be underreported: U.S. rates are likely a floor and not a ceiling. The meticulous tracking in Israel is likely closer to the real figure. Facing a factor-of-5 discrepancy between rates reported by Israel and the U.S., it is not prudent to simply assume that Israel is overcounting myocarditis, rather than the other way around.
If you change even one assumption, the CDC's model tips. Using the CDC's own framework of risk and benefit, key differences tip the calculus. First, the comparison doesn't have to be either two doses or no doses. We can also consider just a single dose. Dose two is associated with greater rates of myocarditis, and one dose of an mRNA vaccine has strong protection (over 90% for severe outcomes) -- even against novel variants such as Delta. If you do this, the calculus tips. Second, building on this model, if one assumes rates of myocarditis documented in Israel, accepting the hypothesis that VAERS underestimates risk, it gets even worse. One of us (Wes Pegden, PhD) re-ran the CDC's analysis accounting for this, which shows that second dose vaccination is unfavorable at young ages. Finally, the CDC's analysis uses SARS-CoV-2 rates from the past -- when fewer adults were vaccinated. Rates might rise in the fall, but that's unclear.
Figure by Wes Pegden, PhD
The CDC did not consider alternative strategies. The decision facing the CDC is not whether or not COVID-19 vaccination in children is generally a good idea. Most immediately, it is whether kids ages 12 to 15 should continue to receive second doses. A range of vaccination strategies are possible in children. Believing that COVID-19 vaccines can be valuable even for healthy children is different from thinking we cannot afford to proceed cautiously. Above all, it does not mean CDC should feel a need to stay the course with second doses whose marginal risks in teens appear likely to exceed their marginal benefits. Manufacturers could also reconsider the dose given to young people under 25 years old. Children's vaccination trials currently underway use lower doses than the adult studies; perhaps a lower or intermediate dose of vaccine could preserve most of the anti-COVID-19 benefit while avoiding the myocarditis risk. The CDC did not explore this option. And notably, dose optimization is an area of drug development for which there is a lot of room for improvement.
The CDC is not accounting for COVID-19 risk factors. Vaccination strategies for young people should be responsive to risk factors that place children at elevated risk of severe COVID-19 disease. While it is true that some cases of multisystem inflammatory syndrome in children (MIS-C) are idiosyncratic -- occur even in healthy kids -- the bulk of adolescent hospitalizations are among individuals with pre-existing risk factors. In contrast, the risk of myocarditis is entirely idiosyncratic and can strike anyone, including healthy adolescents at very low risk of severe disease. Vaccinating those at high COVID-19 risk, but not all young people, is a strategy that must be considered when balancing tradeoffs, as the harms versus benefits to healthy children are different than for kids with risk factors.
The CDC is not factoring in natural immunity. It is hard to believe that the risk benefit balance favors a 15-year-old young man who has recovered from COVID-19, and who has detectable antibodies, getting two doses of an mRNA vaccine. Such an individual is accepting a non-negligible risk of myocarditis, with limited upside in terms of decreased risk of severe infection. If the CDC recommends vaccination for these children, it is imperative they weigh benefits versus harms in precisely this population, which, to date, they have not presented.
Immediately after the ACIP meeting, various agencies and professional societies released ajoint statementarguing that the benefit of vaccination far outweighs the risk in all age groups and demographics. Yet, our analysis suggests this is a premature conclusion. It relies on models that use outdated COVID-19 risk rates -- the on-the-ground rates in the moment are far lower, shifting the harm/benefit calculus to harm. It assumes two doses or none at all are the only options. It does not tailor recommendations by sex, natural immunity, or even comorbidities. We acknowledge there are individual and community level benefits to vaccination that extend beyond preventing hospitalizations and are an important part of the discussion. But these omissions from ACIP/CDC are problematic.
The stakes of this decision are no small thing. Even ACIP acknowledged there is a lot we still do not know about myocarditis after vaccination. There are additional cases being adjudicated, including serious ones, and there are no long-term follow-up studies yet to determine, for example, whether documented evidence of myocardial scar may portend an increased risk of arrhythmias. The ACIP and CDC discussion around vaccinating young teenagers, specifically boys, left out reasonably middle ground positions.
True vaccine proponents -- as all of us are -- understand the best thing we can do for vaccines is deploy them in a way that maximizes benefit and minimizes risk. This is crucial to protect health and also to ensure public confidence in the safety of vaccination. The current CDC guidance is not that. It needs to be revisited.
Vinay Prasad, MD, MPH, is an associate professor in the Department of Epidemiology & Biostatistics at the University of California San Francisco. Ramin Farzaneh-Far, MD, is a cardiologist and drug-developer based in Boston. Wes Pegden, PhD, is a mathematician at Carnegie Mellon University. Venk Murthy, MD, PhD, is a cardiologist and associate professor of Medicine at the University of Michigan. Amy Beck, MD, MPH, is a pediatrician and associate professor at the University of California San Francisco.
Disclosures
Prasad has relationships with Arnold Ventures, UnitedHealthcare, eviCore, and New Century Health. Murthy owns stock in Eli Lilly, Pfizer, Johnson & Johnson, and Merck, which are marketing or are developing products related to COVID-19.
