Deerfielders Weigh in on a Safe Return to Work Policy Amid Covid-19 Crisis

Antibody testing provides a data-driven path to getting people back into the economy

The availability of point of care antibody testing—also known as serological testing—may provide a feasible roadmap for getting people back to work safely following the COVID-19 crisis, according to an editorial published in the journal Contemporary Clinical Trials Communications.

“You can’t stop the economy forever,” asserted Governor Cuomo in a recent news conference, according to STAT. “So we have to start to think about, does everyone stay out of work? Should young people go back to work sooner? Can we test for those who had the virus, resolved, and are now immune, and can they start to go back to work?”

Regardless of whether they already have immunity to the virus, millions of Americans may try to return to work, potentially undoing all the benefits of the shutdown, suggests the editorial. 

Antibody testing, the authors argue, could clarify a person’s status quickly in real-time and reveal whether they have been exposed to COVID-19. Accordingly, a person who mounts an IgG positive response (suggesting the presence of immunoglobulin G antibodies) would most likely now be immune to the virus and an IgM positive result would point to the process of developing immunity in someone who more recently became infected.

“Unlike the PCR tests (a measure of virus material), the immediate results and unconstrained supply of antibody tests could fundamentally change the way we manage this epidemic,” says Robert Jackson, MD, a co-author of the paper. “And from an economic perspective, it could lead to a tractable path for people to return to work. Collecting the data and tracking individuals longitudinally, in order to confirm the hypothesis, will be necessary.”

And barring any HIPAA concerns, the authors propose that persons with positive antibody tests during periods of social distancing could get a bracelet, which indicates that they are immune-protected and can return to work. Those without a bracelet would still be asked to practice social-distancing and not yet resume their normal activities. But this approach could potentially get at least some portion of the economy back running again, suggests the authors.

According to the authors, the antibody tests are cheap, easy to administer, and could be made available at every hospital.

“Broad testing is in society’s best interest,” says Alex Karnal, a co-author of the editorial. “Until we make serological tests available in a robust way, it’s as if we are flying a plane without navigation.”

Authors of the editorial, titled, “Let’s Get Americans Back to Work Again,” are: Alex Karnal, Partner and Managing Director; Robert Jackson, MD, Partner and Chief Science Officer; and Joe Pearlberg, MD, PhD, Vice President of Scientific Affairs, all at Deerfield; and Amitabh Chandra, PhD, McCance Family Professor at Harvard Business School and Weiner Professor at the Harvard Kennedy School.

Deerfield Contributes Insights to Peer-Reviewed Study on Access to Life-Saving Drug, Buprenorphine, Examining Growth and Distribution of Waivered Providers

Despite Evidence Showing the Opioid Crisis Disproportionately Affects Rural Areas, Prescriber Growth There Remains Considerably Slower

Despite Evidence Showing the Opioid Crisis Disproportionately Affects Rural Areas, Prescriber Growth There Remains Considerably Slower 

While there has been an uptick in the number of U.S. clinicians having waivers to prescribe the potentially life-saving drug, buprenorphine, the total number of waivered prescribers in 2017 still represented fewer than 10 percent of all primary care providers, found a report published online in the January 7 issue of the Annals of Internal Medicine.

Moreover, although rural communities have been shown to be disproportionately affected by the opioid epidemic, the growth in the number of providers having this required certification there remains strikingly low, compared to more urban areas. Authors from the RAND Corporation suggest a need for more targeted efforts to increase access to the medication.

To assess the growth in buprenorphine-waivered providers by region and demographics, the investigators leveraged insights from analysis performed by the Deerfield Institute.

Tapping population estimates from the 2010 U.S. census and total physicians per capita, the researchers calculated the total number of waivered providers per 100,000 from 2007 to 2017. Statistics from the Census Bureau were also used to determine per-capita sociodemographic characteristics.

Over the decade studied, the researchers found that the number of waivered providers, in general, increased from 3.80 to 17.29 per 100,000 persons. Growth rate of waivered providers was markedly slower in small, nonmetropolitan areas, as it was in communities with lower levels of education.

The Food and Drug Administration approved buprenorphine for treating opioid dependency in 2002. According to Kaiser Health News, once physicians secure the waiver, they can prescribe buprenorphine in a range of settings, including primary care offices, community hospitals and correctional facilities. Compared with methadone, Buprenorphine is less likely to result in fatal overdoses.

The federal government is undertaking a number of efforts to increase the amount of buprenorphine prescribers.

More details on the research may be found here: Annals of Internal Medicine.

The authors of the paper are Ryan K. McBain, PhD, MPH, Andrew Dick, PhD of the RAND Corporation in Boston, Massachusetts and Mark Sorbero, MS, and Bradley D. Stein, MD, PhD of the RAND Corporation in Pittsburgh, Pennsylvania.

Afib treatment advances publish in prominent medical journals

Real-time feature of Acutus’ AcQMap results in improved patient outcomes

A clinical trial investigating Acutus’ AcQMap showed that this novel imaging and mapping system safely guided cardiac ablation resulting in a 12-month freedom from recurrent atrial fibrillation (AFib) in 73 percent of patients with persistent atrial fibrillation.

The results, published in the July 1, 2019 issue of the Journal Circulation: Arrhythmia and Electrophysiology were first reported earlier this year in a late-breaking trial at the 24th Annual AF Symposium in Boston.

Known as UNCOVER-AF, the trial prospectively studied the safety and efficacy of the AcQMap in 127 patients at 13 sites in Europe and Canada – 98 percent of whom achieved a normal heartbeat upon completion of the procedure.

Characterized as an irregular heartbeat, AFib is the most common type of heart arrhythmia and could greatly increase a person’s risk of developing a severe stroke. Cardiac ablation is a procedure that can reduce the risk, yet traditional ablation procedures often fail to achieve long-term absence of AFib, resulting in repeat ablation procedures.

With its precision ultrasound and high definition re-mapping capabilities, AcQMap helps inform physicians in real time who can strive to improve outcomes by checking their work after each ablation.

Adapted from Acutus’ news release: Publication of UNCOVER AF Study in Circulation Demonstrates Impact of Charge Density Mapping During AF Ablation

Acutus has been a Deerfield portfolio company since 2016.  

Farapulse PFA shown as potential alternative to existing ablation procedures

A method of non-thermal field ablation demonstrated safety and efficacy in clinical trials comparing outcomes of the modality to those seen with traditional thermal approaches in patients with paroxysmal atrial fibrillation, or episodic AFib.

The results of the first-in-human trial were reported in an online early version of the manuscript that is slated to publish in the Journal of the American College of Cardiology.

Called pulsed field ablation (PFA), the alternate modality was shown to successfully target heart tissue without damaging adjacent structures like the esophagus or phrenic nerve – a shortcoming of standard ablation therapies, including radiofrequency (via heat) and cryotherapy (by way of freezing).

In 81 patients, 100% of pulmonary veins (PV) were specifically isolated with three minutes of PFA time per patient. Furthermore, long-term remapping procedures demonstrated that the rates of durable PV isolation improved with successive waveform modifications with the most optimized PFA group demonstrating 100% durability.

The rate of primary safety events was low at 1.2%, and with no subsequent primary adverse events during follow-up.

Farapulse has been a Deerfield portfolio company since 2017.

Enriched enrichment strategies identified by Deerfielder Ming Zhu, PhD

In research that could potentially help increase the efficiency of drug development and support precision medicine, Ming Zhu, PhD, identified ways to further enhance FDA-proposed enrichment strategies. Ming presented his findings in early July at the International Chinese Statistical Association (ICSA) conference in China.

In an effort to improve efficiency of drug trials, the FDA first created its enrichment strategy guidelines in 2012.

The FDA defines enrichment as the “prospective use of any patient characteristic to select a study population in which detection of a drug effect (if one is in fact present) is more likely than it would be in an unselected population.” Examples of patient characteristics include demographic, pathophysiologic, historical, genetic or proteomic, clinical and psychological.

As a part of his analysis to inform on potential areas for strengthening these guidelines, Ming compared the enrichment strategies employed in several clinical trials, while closely reviewing and factoring in the respective study design, the statistical analysis used, along with lessons learned from the trial’s success or failure.

Among Ming’s recommendations are determining the suitability for the disease area in question, adapting quickly from previous studies and enhanced communication with regulatory agencies, when considering an enrichment strategy.

With regard to adapting quickly, Ming discussed a successful phase 3 trial that had benefited from information just released from another trial, pointing to the importance of staying abreast of and acting quickly on related, emerging evidence. In this example, the newly reported data informed on the enrollment of a more enriched study population for the current trial.

Ming emphasized that having early and open communications with regulatory agencies are critical for sponsors in order to secure endorsement of the planned enrichment strategies and statistical methods before undertaking the pivotal trials. As a case in point, Ming cited successful clinical programs that progressed all the way to regulatory submission, only to be rejected when the agency found the enrichment strategies applied to be unacceptable.

He hopes that his research will provide helpful insight into enrichment design and guidance for clinical investigators to develop appropriate strategies toward improved probability of success of clinical trials.

Broad scientists oust Alzheimer’s risk gene in a lab dish by revising DNA

Photo Courtesy of Stephen Dixon/the McGovern Institute

The CRISPR family enzyme CAS13 (pink) uses a special guide (red) to target RNAs in the cell (blue). Broad Institute scientists used a new model of CRISPR, CAS13, to try to eliminate a genetic risk for Alzheimer’s disease, they report in the journal Science.

With a newly adapted CRISPR tool, researchers out of the Broad Institute of MIT and Harvard, have stamped out an Alzheimer’s threat in cells by revising RNA, rather than permanently editing DNA.

The findings were reported in the July 11, 2019 issue of the journal Science.

Feng Zhang, PhD and colleagues illustrated the promise of the new CRISPR platform, CAS13, by deactivating the APOE4 risk gene and changing it to APOE2, the rarer variant (which is protective and may actually decrease a person’s risk for Alzheimer’s: Science). Long viewed as one of the biggest risk factors for Alzheimer’s – APOE4 is also associated with the most common form of the disease.

Because protein-coding RNA is transcribed from genomic DNA, this technique offers the potential to correct disease-causing mutations at the RNA level without the possible risks of making permanent changes to the genome. In addition, in some cell types, particularly postmitotic cells such as neurons, it is difficult to edit genomic DNA using earlier CRISPR approaches. Therefore, CAS13 represents a potential new strategy to treat devastating diseases that affect the brain, including Alzheimer’s.

The new advance, called RESCUE for RNA Editing for Specific C to U Exchange, builds on REPAIR, a technology developed earlier by Zhang and his team that changes adenine bases into inosine in RNA. The scientists took the REPAIR fusion and evolved it in the lab until it could change cytosine to uridine.“Development of RESCUE demonstrates the power of protein engineering of natural processes,” said Deerfielder Bob Jackson, MD. “The ability of RESCUE to edit from C to U increases the number of pathogenic mutations targetable by RNA editing. It also adds capacity to potentially edit important signaling residues.”

CRISPR refers to Clustered Regularly Interspaced Short Palindromic Repeats that occur in the genome of certain bacteria, from which the system was discovered. Often thought of as “molecular scissors”, the CRISPR technology enables researchers to remove, add or alter specific DNA and RNA sequences in the genome of higher organisms, with the goal of curing disease.

The Broad has been a Deerfield collaborator since 2017: Broad Institute and Deerfield Management launch innovative partnership to tackle serious unmet medical needs

Adapted from MIT news release

V-Wave scores FDA breakthrough status on its heart failure shunt

V-Wave, Ltd., recently announced that it received the prized FDA Breakthrough Designation for its heart failure shunt. Breakthrough designation is one of the highly sought pre-approval stamps that the FDA can place on a device.

According to the FDA’s website, it is granted when the device “provides for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions” (than what is currently available). The program aims to provide patients and health care providers with more timely access to medical devices “by speeding up their development, assessment and review,” including prioritized review all the way through to market approval.

V-Wave’s minimally-invasive implanted interatrial shunt for the treatment of patients with severe symptomatic heart failure is designed to regulate left atrial pressure, the primary cause of breathing difficulty and hospitalization due to worsening heart failure.

“In addition to validation of the potential impact of this technology, breakthrough status will facilitate a timely regulatory review and solve a major issue with medical device investments, namely that reimbursement will effectively be secured immediately upon approval,” said Deerfielder, Andrew ElBardissi, MD, who serves on the Company’s board of directors.

The shunt is currently being evaluated in a global, randomized, controlled, double-blinded, 500 patient pivotal Investigational Device Exemption trial called RELIEVE-HF. The study is enrolling advanced heart failure patients with preserved or reduced left ventricular ejection fraction who

remain symptomatic despite the use of guideline directed medical and device therapies.

An ejection fraction is an important measurement of how well the heart is pumping and is used to help classify heart failure and guide treatment. In a healthy heart, the ejection fraction is 50 percent or higher – meaning that more than half of the blood that fills the ventricle is pumped out with each beat.

According to the Centers for Disease Control and Prevention, nearly 6 million adults in the United States have heart failure and about half of these individuals die within 5 years of diagnosis. Heart failure costs the nation an estimated $30.7 billion each year.

Achieving this status means that the device also met at least one of the following FDA criteria:

  1. It represents breakthrough technology;
  2. No approved or cleared alternatives exist;
  3. It offers significant advantages over existing approved or cleared alternatives; and
  4. Availability of this device is in the best interest of patients.

V-Wave, Ltd., a privately held medical device company, has been a Deerfield portfolio company since 2018.

Adapted from company news release: V-WAVE’S INTERATRIAL SHUNT RECEIVES FDA BREAKTHROUGH DEVICE DESIGNATION FOR HEART FAILURE:

https://www.fda.gov/medical-devices/how-study-and-market-your-device/breakthrough-devices-program

https://www.mayoclinic.org/diseases-conditions/heart-failure/symptoms-causes/syc-20373142

https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm

Generic drug prices are actually falling

Despite drop, patients continue to get hit with high prices at the pharmacy for reasons that may have little to do with pharma

As pharma gets slammed for egregious pricing of life-saving medications and stories continue to make headlines – generic drug prices are actually falling.

That’s not to say that consumers aren’t still being saddled with high costs at the pharmacy, but a July 2019 paper by the National Bureau of Economic Research (NBER) that reviewed the pricing patterns of generic drugs suggests that other factors may be at play.

Although the U.S. generic prescription pharmaceutical market continues to drive overall prices downward, reductions in pharmacy price are not fully passed to patients, according to the NBER researchers.

One contributing factor to patients not reaping as much of the benefit of the generic price declines, the authors suggest, is the increase in cost-sharing: the practice of insurers offering plans that increasingly shift costs from insurers to consumers.

“Plan sponsors are opting for benefit designs that have consumers sharing a higher percentage of costs. The result is out-of-pocket costs falling less than overall generic drug prices,” said Deerfielder Vince Mellet. “Even so, the prices of generic drugs went down.”

To put these generic price increases into context, the investigators developed two price indices that capture prices of generic prescription drugs paid by consumers of private health insurance plans.

The first, direct out-of-pocket CPI, measures consumers’ direct out-of-pocket payments to the dispensing pharmacy. The second, total CPI, represents the total revenues received by the dispensing pharmacy – the consumers’ direct out-of-pocket payments, plus the amount paid to the pharmacy by the insurer on behalf of the customer.

Based on the analysis, the researchers found direct out-of-pocket CPI for generic prescription drugs declined by approximately 50 percent between 2007 and 2016, while the total CPI fell by nearly 80 percent over the same period. The investigators partly attribute the smaller reduction in the direct out-of-pocket CPI, compared to the total CPI, to consumers’ increasingly moving away from fixed copayment benefit plans to exclusively coinsurance or a mix of coinsurance and copayments.

While consumers are encountering more cost-sharing that shifts more of the drug cost burden on to them, the researchers report that, on balance in the U.S., consumers have still experienced significant price declines for generic drugs.

Given their findings, the investigators suggest that overall affordability is not the primary issue in the generic drug market and that this segment of the U.S. prescription market is not responsible for the reported growth in prices and spending for prescription drugs overall.

To get the full picture on prices in the U.S. generic prescription industry, the NBER researchers recommend taking a closer look at all components of the entire generic supply chain, from manufacturer, wholesaler, pharmaceutical benefit manager, insurer, to retailer.

To view the full paper, titled “The Price to Consumers of Generic Pharmaceuticals: Beyond the Headlines”, visit: https://www.nber.org/papers/w26120

© 2019 by Richard G. Frank, Andrew Hicks, and Ernst R. Berndt.