27
Jul
2021

An Industry that Depends on Diversity Should Defend It

Paul Hastings, CEO, Nkarta Therapeutics

[Editor’s Note: I asked Paul to write in response to a biotech executive who’s marketing a new book that claims diversity and inclusion in business is “the defining scam of our time.”]

As CEO of a cell therapy company, I know that the human immune system is a pointillist masterpiece, containing trillions of B and T cells with unique antigen receptors that allow them to latch on to and neutralize endless permutations of potential threats.

Within the human body, our diversity is – quite literally – our greatest strength.

The COVID-19 pandemic, for all the tragedy it has wrought, helped ignite two long-overdue conversations in America: one about health equity and another about the value of diversity and inclusion in a time of heightened attacks against those who identify, look or love differently.

In so many ways, biopharma CEOs sit at the intersection of both this new disease and this new dialogue. I know many CEOs and industry leaders who have been championing diversity and inclusion long before it was as popular to do so, but I celebrate the current focus on addressing systemic barriers. As a an openly LGBTQ CEO and a longtime warrior in the diversity trenches, I’m endlessly proud that a growing majority of my biopharma CEO colleagues are embracing this leadership role.

Some critics don’t believe that advocating for diversity and inclusion is in the job description of biotech CEOs and dismiss our efforts as “woke” and insincere.

Here’s what I believe: To lead a company charged with creating “living” biologic medicines in 2021 is to understand, as a fundamental matter of science, the life-sustaining value of biological diversity. The value of diversity is equally self-evident when we look up from our lab benches and look out at our colleagues around the conference-room table.

To create a culture of innovation, experience as a five-time biotech CEO has taught me to insist on teams full of people with different backgrounds, experiences, perspectives and ideas. CEOs who fail to proactively seek out such synergies aren’t just “unwoke”. In my opinion, they’re asleep at the wheel.

The truth is, some biopharma leaders have hit the snooze button for far too long on diversifying clinical trials, on building inclusive leadership teams, on hiring outside of homogenous comfort zones and on assembling culturally competent teams that can understand and meaningfully connect with underserved patient populations.

Now, from the ashes of the COVID and George Floyd tragedies, progress has a chance. There is no filibuster in the biopharma C-suite. Industry CEOs have great power to effect change and be part of an industrywide effort to invest in health equity to regain public trust and affection.

We are in the midst of a paradigm-shifting global pandemic that preys on the immunocompromised, the underinsured and the unseen. Conversations are changing. Companies are engaging contract research organizations to amplify efforts to reach diverse populations. Health equity and Corporate Social Responsibility (CSR) budgets are becoming more substantial line items. Investors now demand it.

The biotech industry is charting a more compassionate, inclusive, patient-focused course, one Zoom meeting at a time. If dedicating time and resources to achieve that kind of overdue progress is “woke,” I don’t ever want to go back to sleep.

Paul Hastings is the CEO of Nkarta Therapeutics in South San Francisco.

26
Jul
2021

Career Arc of a Biotech Leader: Sue Desmond-Hellmann on The Long Run

Today’s guest on The Long Run is Sue Desmond-Hellmann.

Sue — and I don’t say this about many people — is a biotech industry legend.

Sue Desmond-Hellmann

Sue is an oncologist and a public health professional by training. She made her name in biopharmaceuticals at Genentech from 1995-2009 — the glory days when it became the world’s most important developer of new cancer drugs.

She was part of the leadership team when the company developed the original targeted antibodies for cancer – Rituxan, Herceptin, and Avastin.

After Genentech, Sue served as chancellor of UCSF, and then worked as CEO of the Bill & Melinda Gates Foundation until January 2020.

Currently, among other things, Sue is a board member for Pfizer, and is an advisor to GV, the venture capital firm formerly known as Google Ventures.

In this episode, we talk mostly about Sue’s early career – growing up, becoming a doctor, working on the frontlines of the AIDS epidemic, and finding her way into industry. We talk some toward the end about her time at Genentech.

Before we dive in, a word from the sponsor of The Long Run.

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Now please join me and Sue Desmond-Hellmann on The Long Run.

20
Jul
2021

Why We Need mRNA Vaccines in Africa, and For All Who Are Immunocompromised

Larry Corey, MD

The HIV pandemic, and COVID-19 pandemic, are intersecting.

The relationship between the two conditions is creating an epidemiological synergy that is starting to translate into additional misery for humankind.

If we can better understand this phenomenon, we can think more clearly about how to better protect the most vulnerable populations among us – people with HIV, and millions of others who are immunocompromised. We have seen overlapping epidemics before, and can draw from that experience.

Let’s start with HIV. Individuals living with HIV have a degree of immunosuppression which varies based on their therapy and disease course. If the disease course is well controlled and fully virologically suppressed on antiretroviral therapy, there is evidence to believe that these patients are at a normal risk of acquiring and controlling COVID-19, much like others in their families and communities.

This analogy is partially accurate in that those living with HIV can, because of their medicines, have obesity, diabetes, and increased lung disease, which are all predispositions or comorbidities associated with severe COVID-19.

Importantly, there are subsets of persons living with HIV, including those who are immune deficient with low T cell counts, those with viremia due to drug-resistant HIV viral strains, those not receiving or not taking antiretroviral therapy; and the many millions we know are living with undiagnosed HIV infection, including those recently infected.

These persons are subject to acquire persistent, prolonged COVID-19 infection, akin to organ transplant recipients and severely immunosuppressed cancer patients.  

There are many causes of immune deficiency, but in many countries, HIV infection is among the most common.

A recent case report by Karim et al. from South Africa, the country with the largest percentage of the population living with HIV of any country, described a case of HIV infection in a person who had very low CD4 counts due to resistant virus and a lack of compliance who developed COVID-19. Over a period of 200 days, this patient—who was ambulatory, living in the community, and without serious symptoms—shed COVID-19. The person had mild illness early on, which is why they were observed, and because of HIV, follow-up care ensued. The investigators had samples from the patient, and they shed COVID-19 at high titers, showing the development of multi-mutational changes in the virus over time. Mutational changes that essentially recapitulated the Beta variant, which has 9 to 11 different mutational changes from the original ancestral strain.

This is a single case, but it’s important because it illustrates a broader issue at work in our communities.

Individual patients living with HIV and compromised immune systems who have this prolonged shedding pattern can result in the kind of mutational changes that lead to germination and spread of variants of concern.

This case is illustrative because it’s not rare. Out of the estimated 38 million people living with HIV worldwide, South Africa alone has more than 16 million. In South Africa, that means one out of every four of its 65 million people are living with HIV.

So okay, the two epidemics are intertwined, what’s the concern? The concern is that these people will suffer more serious COVID-19 cases and that they may serve as the potential unwitting source of super-spreading events of new variants through household and community contacts.

As the greatest population of persons living with HIV is in sub-Saharan Africa, where vaccination rates are currently less than 2% of the populace, this continual reservoir of variant generation is and should be of concern to all of us. We need to recognize that we do not have a demonstrably effective vaccine against COVID-19 among persons living with HIV. People with immunocompromised profiles weren’t included in the well-controlled vaccine studies of the past year, when speed of enrollment was of the essence (see June 29 article in Timmerman Report).

While we lack comprehensive data, we have good reason to be concerned about vaccine efficacy in immunocompromised groups. The data that we have from the Novavax study in South Africa showed absolutely no efficacy against COVID-19. In the Ensemble Johnson & Johnson (J&J) study, too few cases were acquired to adequately evaluate the effectiveness of the one-dose J&J vaccine. And in the Moderna trial, no cases of COVID-19 were reported in the 150 HIV+ recipients who received vaccination. The reason for the lack of efficacy of the Novavax vaccine is puzzling and worrisome, as the post-vaccination binding antibody titers were well above natural infection and in the range associated with reasonable efficacy (median 33,000).

So, what’s going on here? The answer is, I don’t know the reason for lack of effectiveness, but I do know that the mRNA vaccines offer the most immediate solution to this major hole in the public health control of COVID-19 variants.

The data suggest that we need to take our most potent vaccines—mRNA or perhaps two doses of the J&J vaccine or a heterologous “mix-and-match” prime-and-boost with one of the vaccines being an mRNA vaccine—into areas of the world where there is HIV.

We need to urgently take steps to evaluate if our best vaccine regimens are able to effectively prevent acquisition of COVID-19 in all persons living with HIV, but especially among those with uncontrolled HIV.

This is the kind of urgent, heavy lifting that only the US government can do in an emergency.

The tale of these two intersecting epidemics needs a better ending than what we—as a global community—are currently creating. The Delta variant epidemic is rapidly illustrating that chasing variants is not a successful strategy. The Delta variant has swept through countries like the UK, Israel, and South Africa in four to eight weeks and is approaching the predominant variant in the United States at a speed that even with RNA technologies, we cannot keep up. Our approach must be to slow down the generation of these rapidly doubling super-spreading micro-epidemics of infection among unvaccinated persons.

The equation today among those unvaccinated individuals is not whether you will get COVID-19 infection but when you will get it. Slowing it down requires our best vaccine strategies. It’s certainly not too late. But we need both studies and implementation of our most potent vaccines and vaccine regimens to be applied to all of our immunosuppressed populations, the largest of which is HIV, for us to have a globally effective strategy.

Dr. Larry Corey is the leader of the COVID-19 Prevention Network (CoVPN ) Operations Center, which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic and the Chair of the ACTIV COVID-19 Vaccine Clinical Trials Working Group. He is a Professor of Medicine and Virology at University of Washington and a Professor in the Vaccine and Infectious Disease Division and past President and Director of Fred Hutchinson Cancer Research Center.

19
Jul
2021

Investing at the Nexus of Biology & Technology: Jenny Rooke on The Long Run

Today’s guest on The Long Run is Jenny Rooke.

Jenny is the founder and managing partner of San Francisco-based Genoa Ventures.

Jenny Rooke, founder and managing partner, Genoa Ventures

I’ve been wanting to invite Jenny on the podcast for a while. Back in 2018, I profiled her as one of “Nine VCs Who Matter, But You Never Read About.”

As I wrote then:

VCs take on lots of different types of risk. There’s biology risk (something can’t be reproduced from mice to humans). There’s management risk (sometimes you back bad executives). There’s market risk (maybe the market won’t buy what you’re selling at your preferred price). There’s syndicate risk (your co-investors might run out of money or lose faith, forcing you to prop up portfolio companies if you want to keep them alive to the next milestone).

What you seldom see are VCs who shoulder a more profound type of risk, not just by starting their own firm, but by starting a venture firm with an unproven business model.

She started her firm by building the largest life science syndicate on AngelList, not by going to the usual big pension and endowment funds that typically invest in VC funds as limited partners.”

Here’s how she describes her approach:

“I’m particularly motivated by novel research platforms because part of what surprised me about lab work was how manual, and slow, and low through-put a lot of available tools were for doing science, so when I see companies that are trying to develop new tools that make more and better data for researchers that gets me excited.”

How’s it going so far?

Like any early-stage VC, it takes a while to build a track record.

Two of Jenny’s big investments from the early days of Genoa are emerging – Emeryville, Calif.-based Zymergen, an industrial biotech company, and Berkeley, Calif.-based Caribou Biosciences, a company that uses CRISPR editing for cell therapies.

Zymergen went public in April, and now has a market valuation of $4 billion. Caribou Biosciences recently filed IPO paperwork to raise up to $100 million.

It took a lot of guts and creativity to do what Jenny has done, and continues to do.

Before diving into her story, a word from the sponsor of The Long Run.

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With SYNTAX, researchers can accelerate discovery with DNA on-demand.

For more information on DNA Script, please visit www.dnascript.com.

Now please join me and Jenny Rooke on The Long Run.

19
Jul
2021

From Delta…to Omega?

Otello Stampacchia, founder, Omega Funds (illustration by Praveen Tipirneni)

I hope you are all enjoying your summer break with (finally) being able to see friends and family (and fine food NOT from a delivery service).

You are? Great!

Now let me spoil some of that for you.

  • This pandemic is not over

I understand the inclination to consider the pandemic behind us. In large parts of the US / North America and in (most of) Western Europe, vaccines (largely the very effective mRNA kind, with the UK being a notable exception) have been rolled out quite effectively and have now been administered to large percentages of the elderly and of the “at risk” population.

Cases and deaths have been decreasing for months in the same locations and are now a fraction of the (horrific) numbers we had last winter.

However, the (now infamous) Delta variant (originally discovered in India) is spreading at accelerating rates across the world. This includes (worryingly) countries who previously faced other variants of concern (VoCs), such as Alpha (discovered in the UK) and Beta (discovered in South Africa): it is particularly concerning to notice the exponential spread of Delta in the UK, a country that is now in its summer, had already been ravaged by Alpha last winter, and has fully vaccinated most of its vulnerable population with the adenoviral vector-based AstraZeneca vaccine.

I do understand the impulse to rush to Wembley to watch the home team lose to the Italians, but still. Similarly, South Africa has been facing an exponential growth in cases since June.

I can already hear you: “The increase in the number of cases is not resulting in an increase in hospitalizations and deaths. That link has been broken!”

First of all, and not to repeat myself: increases in cases appear earlier than increases in hospitalizations, which themselves lag behind an increase in deaths, each by 2-3 weeks. We already are noticing meaningful increases in hospitalizations amongst the unvaccinated / younger populations in the UK and US.

It is also true that the young (<50 years old) are at lower (relative) risk of hospitalization and severe disease. That said, the absolute number of people who will now potentially be infected is higher since Delta is super contagious AND vaccination rates are low amongst the young.

Second of all:

  1. it is TRUE that doubly-vaccinated, “healthy” people are strongly protected from severe symptoms and hospitalizations (even from Delta infections); that said, and as eloquently said by Larry Corey in this June 2021 Timmerman Report, there are UP TO 15 MILLION PEOPLE, in the US alone, who are immunocompromised / immunodeficient. These are cancer / HIV / transplant patients, amongst others. Vaccines have not been tested in clinical studies in these populations. There is now a large body of evidence that antibody responses in these groups wanes fairly quickly even after double vaccination. T cell response might last longer than antibody levels and might confer some protection, but we simply do not know how much or for how long: it remains unclear the amount of protection even mRNA vaccines might be able to provide, in the long run, to these patients;
  2. Even in the US and Western Europe, there are significant pockets of vaccine-deniers: refusing to be vaccinated is already resulting (in the US especially) in significant increases in hospitalizations in certain locations. This fall we will have also to contend (again) with more indoor transmission and the re-emergence of other transmissible viruses (flu, RSV, etc.) (FYI: I am NEVER shaking another person’s hand again.

I doubt we will see a repeat of the horrific statistics we saw last winter in the US / Western Europe (vaccination levels were almost nil back then).

However, even now, the US is tracking just below ~300 deaths / day from the pandemic, almost entirely in unvaccinated individuals. And we are in the summer, where opportunity for super-spreader events are much more limited. Without a new surge in vaccinations, and with the Delta variant in wide circulation, we could very well see a corresponding increase in deaths this fall when more people are gathering indoors.

Now, I know this is not a very popular point of view, but let’s try to forget American exceptionalism (for just a minute) and look at what is happening in other countries who do not have the luxury of having access to efficacious vaccines for their population.

Across the world, and in particular in South America, Southeast Asia, and Africa, the conditions are horrific. A lethal combination of insufficient vaccination levels (because of lack of supply), variants spreading (Delta above all, with Lambda being a possible concern in South America) and winter kicking in in the Southern hemisphere, is wreaking havoc on these countries.

Even countries who successfully contained the virus early on (Australia, Japan, Indonesia, Vietnam, etc.) are being forced into repeated lock-downs because of the lack of vaccine supplies and the spread of the Delta variant. South Africa has <3% of its population fully vaccinated, Indonesia <6%: both countries currently report record rises in cases, at levels that are multiple times higher than last January.

  • The increasing risk of more variants of concern

As I mentioned in February, (I am NOT going to change my already tragic first name to Cassandra (thank you very much!): there are no precedents in humanity’s history for a pandemic confronted in similar conditions: 8 billion susceptible individuals, many with co-morbidities (see below), and relatively unfettered, almost instantaneous travel between countries. The Delta variant was sequenced in Dec 2020, and it has since become the most prevalent variant across the world.

Its evolutionary fitness is something to behold. One study earlier in July from Guangdong found that viral loads in patients with the Delta variant were ~1000 times higher than with previous variants on the day the disease was first detected. It also appears people shed viral particles much earlier when infected with Delta. No wonder we’re seeing Delta spread so remarkably fast.

The one, I believe unprecedented factor that absolutely terrifies me, however, is the almost ideal incubation factory for novel, fitter viruses represented by immunocompromised / immunodeficient individuals.

One case from June might highlight this concern: a 36-year-old woman with HIV from South Africa was diagnosed with COVID and followed by her physicians. The virus was found to persist in her (immunodeficient / immunocompromised) body for over 200 days and to accumulate 32 mutations during this period, 13 to the spike protein and 19 others across the viral genome.

That’s a lot of opportunity, in just one individual, for SARS-CoV-2 to find ways to evade the host’s immune reaction. Now consider how many individuals in modern societies are immunocompromised. The virus has a mind-boggling number of opportunities to develop escape mutations, and it’s moving through large populations at exponential speed.

The only long-term solution for developing countries is to vaccinate their populations as soon as possible: they do not have the luxury of prolonged lock-downs since their governments will not be able to provide the same level of support that Western governments enabled for their workers and economies. Therefore, for the time being, the pandemic will continue to ravage Africa, South America and Southeast Asia with relative impunity.

It is anybody’s guess how long it will take to vaccinate developing countries. We’ve already seen India — the major producer of AstraZeneca’s vaccine for the COVAX facility — halt some of its vaccine exports to better vaccinate its own vulnerable populations. India reportedly made this decision in the aftermath of its tragic Delta-fueled surge this past spring.

A wild guess, but I am thinking it will probably take an additional year / 18 months or so to cover the world with vaccines. And this could be an optimistic scenario, as it assumes a) Western countries avoid falling into more “vaccine nationalism”, as their own populations claim booster shots and b) ALSO that manufacturing has been scaled up.

Add to this timeline the extremely worrying fact that we are still not performing enough sequencing of potential emerging variants (including, and criminally so, in the US), and we might be blindsided again this winter from another variant which might be as infectious as Delta and perhaps better at evading the immune system than Gamma or Beta. I am not sure what the probability of that is. It is far from zero.

By the way, the potential long-term geopolitical repercussions of letting the pandemic ravage uncontrolled in these countries could be absolutely devastating to the current world order. Now, if you want to chat about that, let me know, but I do not want to depress readers any further.

  • Some predictions

I am sure you are, by now, sick of hearing me prophesizing doom and gloom every time that you think you can finally go out on vacation and meet friends. Therefore, before starting my own little break, I am providing below a table describing what might be the short-medium term outlook in different parts of the world.

All this, without being able (of course) to assess the consequences of an “Omega” variant that resists / escapes vaccine-induced immunity. If such a variant emerges, then, as I wrote in my first Timmerman Report on Mar. 10, 2020:  

“May the fates look upon us with mercy”.

 

Follow Otello Stampacchia on Twitter: @OtelloVC

This article expresses the personal views and perspectives of the author. The views and perspectives expressed here do not necessarily represent the views or perspectives of Omega Fund Management, LLC or any officer, director, partner, member, manager or employee of Omega Fund Management, LLC or any of its affiliated entities.

29
Jun
2021

Immunocompromised People Are Vulnerable to COVID-19. We Owe Them Some Answers

Larry Corey, MD

As fully vaccinated citizens in our country and around the globe begin to dip their toes in the waters of a post-vaccination world, there are two groups that deserve greater consideration: immunosuppressed or immunocompromised people.

This is not a small group of people.

Estimates are that about 6.2 percent of adults ages 18-64 in the US are living with weakened immune function, along with about 2.6 percent of children, according to the Centers for Disease Control and Prevention.

The prevalence of immunosuppression appears to be on the rise, as many people are living longer with cancer, HIV, organ transplants, or with chronic therapy with biologic medicines that make people more vulnerable to infections.

Fifteen million people is a large community; people who live in all regions and every city in the US. They are your neighbors, your sister’s friend, the person next to you in line at the grocery store; people who are unlikely to mount strong immune response to COVID-19 vaccines.

They need some extra help from all of us to stay safe.

So let’s talk about COVID-19 prevention strategies for this group of vulnerable people among us. Let’s start with patients who have received donor organs (like kidney or liver transplant recipients) and bone marrow transplants who are on medications that suppress their immune systems (to prevent graft rejection), as well as cancer patients whose immune systems have a reduced capacity to respond to vaccines because they’ve received chemotherapies that kill off many of their infection-fighting white blood cells.

The second immunosuppressed population I’ll discuss in a separate piece, are individuals living with HIV infection.

The global COVID-19 vaccine and prevention story, largely narrated by the data generated from the USG COVID Vaccine (formerly Operation Warp Speed) program, did not include immunosuppressed persons in the clinical trials of the COVID-19 vaccines approved under Emergency Use Authorization in the US.

As the architect of these trials, I need to do some explaining here, especially because as a physician and scientist, I have spent almost all of my career working in developing therapies and strategies to reduce infections in these people.

When we started the clinical trials, we had no idea how effective these vaccines would be. Speed and efficiency in trial conduct were necessary. We needed vaccines for the majority of the US adult population.

We knew that historically immunocompromised people are less likely to respond to vaccines than people with competent immune systems. There was also an issue how to discern vaccine side effects from side effects of all the medications immunosuppressed people take, and what other infections the immunocompromised person may have picked up coincidentally would have in relationship to the vaccine.

For this reason, including these patients in the initial efficacy trials would have complicated the interpretation of side effects and hospitalizations. Moreover, when we initiated the trials in summer 2020, we were concerned about the possibility of vaccine-induced COVID-19 disease enhancement, something we would not want in any person, let alone one who was immune compromised.

Fortunately, this is something we now know has not occurred in any of the vaccine trials.

Excluding immunosuppressed patients from the initial Phase III trials was the correct and necessary decision.

Unfortunately, however, we did not initiate concurrent parallel clinical trials in immunocompromised patients. That left trials in these patient populations to the vaccine makers or other philanthropic or government entities to “pick up” and conduct.

While some trials were started, they have been small and limited in scope. Most importantly, none have been large enough to evaluate vaccine efficacy. Unfortunately, the current state of information on vaccination in organ transplant and cancer patients is an anecdotal collection of small studies showing that vaccines seem to be safe, but, as predicted, elicit reduced levels of immune responses.

The data we have on organ transplant patients who have been treated with standard drugs that deplete B cells (e.g., Rituxan) and high-dose chemotherapy all tell us that at best 50% of persons develop detectable antibodies after two doses of mRNA vaccines.

Having detectable antibodies is a good sign, but we have very sensitive tools that can detect very small concentrations of antibodies. Few of these patients are generating the kind of robust concentrations of neutralizing antibodies that immunocompetent persons are typically able to generate, and which are thought to be necessary to protect against moderate to severe COVID-19.

In many populations like these where B-cell depletion occurs, the percentage of persons with detectable levels of neutralizing antibodies is 20 to 25% at best. Little is known of memory T cell responses in immunocompromised persons. This is an important area for further research, as T-cell responses could provide an important clue into whether the vaccines provide protection that lasts for the long term.

The main problem right now is that there are no data to indicate if the level of immunity reduces infection, or more importantly, if these immune responses are good enough to protect these individuals from hospitalization from severe COVID-19.

This is concerning because when immunosuppressed persons get infected with SARS-CoV-2, they frequently get prolonged, persistent infection. Case reports show patients with COVID-19 infection persisting for 200 days. During that time, the virus is replicating inside them, creating ample opportunity for variants to emerge. These variants often have the characteristic mutational changes associated with variants of concern. There is suggestive evidence that both the Alpha and Beta strains initially emanated from immunosuppressed patients.

Like COVID-19 in immunocompetent persons, the spectrum of illness in immunosuppressed patients is wide. The immunosuppressed patient can be asymptomatic—or mildly symptomatic—and transmit to family and friends and then introduce the variant into the community. Or they can have progressive longstanding pneumonia with prolonged shedding of the virus. Thus, we have a twofold difficulty.

It’s not good that we can’t protect the most medically vulnerable from getting COVID-19, and if they do get infected, they are at risk of progressive pneumonia as well as transmitting these variants to their loved ones and communities.

SARS-CoV-2 as a pathogen shows no beneficence or mercy to the vulnerable.

So, we truly need to find solutions here. Can we develop a vaccination regimen that works for immunocompromised people? Should we give them neutralizing antibodies for prevention, to give them some degree of temporary protection while we vaccinate as many people in the wider population as possible?

What about giving them genetically engineered neutralizing antibodies, plus giving them a vaccine to help them mount their own immune response?

How about trying vaccination first and if that doesn’t work, use long-acting monoclonal antibodies for those patients for whom vaccination has failed?

Vaccinating patients’ loved ones and households certainly is important. And hospitals that care for immunosuppressed persons need to make sure their employees are vaccinated to reduce variant spread.

Yes, in this author’s opinion, there should be mandatory vaccination for hospital employees.

These studies I’m proposing not only need to be about the immune responses to the vaccines as we’ve conducted in other studies, but also about studies of immunosuppressed persons globally where we can evaluate not only clinical efficacy but breakthrough shedding.

Does vaccination eliminate the virus from the nose? If so, then how do new variants emerge? These studies will be a bit more onerous to run than the original Phase III trials, as we’ll need to collect nasal samples on a daily basis to answer this question about viral transmission from the nose. Today, we are vaccinating cancer and organ transplant patients, but without any assurance that they are well protected.

Do we know that two-dose inoculation will afford them the same amount of protection as the rest of their families and communities? The answer is no.

Can vaccinated immunocompromised persons, like the rest of the vaccinated population, take off their masks in most public spaces and move freely throughout their days with greater peace of mind? The answer is, we’re not sure.

These are all questions we need to answer for a population that is not trivial—either in significance or in number. In the US, there are 16 million people living with cancer and at least 1 million organ/bone marrow transplant patients. These are real issues to many US and global citizens, their families, and communities.

We in the medical and scientific community owe them real answers.

Dr. Larry Corey is the leader of the COVID-19 Prevention Network (CoVPN ) Operations Center, which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic and the Chair of the ACTIV COVID-19 Vaccine Clinical Trials Working Group. He is a Professor of Medicine and Virology at University of Washington and a Professor in the Vaccine and Infectious Disease Division and past President and Director of Fred Hutchinson Cancer Research Center.

24
Jun
2021

The Other Half: Decentralized Research is The Path to All-Inclusive Medicine 

Sanskriti Thakur, chief growth officer, Medable

More than half of the U.S. population is projected to be “other than non-Hispanic white” by 2045.

If the current clinical research process doesn’t adapt to these changing population demographics, the life sciences industry will continue developing drugs and devices that are only shown to work for a select few, leaving out the “other half.”

Despite efforts, including those from the U.S. FDA and the Revitalization Act of 1993, which required that clinical trials funded by the National Institutes of Health include women and minority participants, diversity in clinical trials has not substantially improved. At least 83% of research participants are white even as they make up about 67% of the U.S. population. African Americans make up 13.4% of the U.S. population, but only 5% of the people who participate in trials. Hispanics represent 18% of the population but less than 1% of those enrolled in trials.

Participants in clinical trials should reflect the diversity of the population, and not just for altruistic reasons. A lack of representation from minority groups in research has resulted in interventions that have not translated well in the real world. This can even prove harmful in different populations.

For example, 5-Flurouracil, a commonly used cancer chemotherapeutic drug, often exhibits differences in drug response among different populations. A major side effect associated with the drug is the occurrence of hematologic toxicities, including leukopenia and anemia. These toxicities are often found in higher rates in underrepresented populations. Not surprisingly, this fact wasn’t discovered in clinical trials. 5-Flurouracil’s clinical trials were overrepresented with white participants, missing the opportunity to assess the adverse effects in minority groups.

Unexpected safety issues are one of the main drivers of failure in R&D. When data from diverse populations is lacking, additional post-marketing studies are often recommended, adding costs. Yet drugs are still sold, and the cycle repeats.

About 2 million serious adverse events occur each year in the US, and SAEs are responsible for about 100,000 deaths a year, according to the FDA’s Center for Drug Evaluation and Research. We could reduce this toll of suffering and death by more thoroughly testing drug candidates in a representative study population. Instead, we are making drugs for one population. The rest are often not even aware of potentially life-saving clinical research opportunities. Misinformation, politics, money, distance, fear are all contributors to why medicines remain suboptimal. It must change.

Finally, fortunately, the foundation has been laid to make clinical research more accessible with better outcomes. Decentralized clinical trials, hybrid trials, remote clinical trials, adaptive clinical trials – these boundaryless research models are possible now thanks to technology and a patient base eager to use it.

Here are three reasons why an inclusive, adaptive, decentralized model for research is the future: 

1) Patients demand more. For the first time, the masses experienced remote treatment during the pandemic, and they will continue to expect it. In one survey, up to 98% of patients reported satisfaction with telemedicine. In another, 72% of physicians reported similar or better experiences with remote engagement compared with in-person visits. Indeed, patient-centric healthcare is possible with technologies built of human-centered design principles. 

2) The efficiencies are irresistible. The $2.6B+ cost per product for developing drugs is still growing especially where personalization and cell and gene therapies challenge the system. Decentralization breaks from the traditional model to drive costs down by reducing time to market, improving trial efficiency, and enabling better outcomes for a more diverse population. Leveraging hybrid and remote technologies, scientists can test new therapies at pace in smaller but more representative populations without investing in as much brick-and-mortar infrastructure. For instance, community pharmacies and local urgent care centers can become cost-efficient, convenient site locations for certain therapeutics while telemedicine reduces travel and cost burden for patients as well as sponsors.

3) Precision medicine is becoming mainstream. Targeted therapies accounted for just 5% of new molecular entities approved by the U.S. FDA in 2005 but accounted for more than 40% in 2018. That’s great news, but it also makes finding the right patients to fill those niche research opportunities difficult. With advanced technologies now available to include smaller cohorts of patients in these trials, there is an  opportunity to dismantle the current paradigm of clinical research.

Today, three-fourth of companies say they are running “some decentralized trials”, the U.S. FDA is expected to offer new guidance for operating decentralized trials, and 100 industry leaders make up the newly formed Decentralized Trials & Research Alliance (DTRA). Additionally, the continued rise of precision medicine and gene therapies means that diversity in clinical trials is now more crucial than ever to obtain a complete picture of a drug’s safety-efficacy profile. 

The industry is at a critical inflection point. Do we continue to make drugs that treat just half of the population? Or do we adopt new clinical research models that enable better outcomes? We are now able to move science from product to platform, creating technological access to medicine for everyone.

It’s an imperative for health equity. Without it, medicine is not made for everyone.

Sanskriti (“Sans”) Thakur is Medable’s Chief Growth Officer. She most recently served as global life sciences research lead for Accenture. sans.thakur@medable.com.

23
Jun
2021

Biopharma’s Racial Justice Work is a Start. But More Needs to Happen

Stewart Lyman, biotech consultant

Stewart Lyman

Biopharma leaders have pledged to make their companies more diverse and inclusive. MassBio created an open letter on culture, recruitment, development, sustainability and accountability that has been signed by presidents and CEOs of more than 200 member companies.

Large and small companies have described some of their specific efforts in public. Bristol-Myers Squibb aims to double the number of executive roles for Black and Latinx employees; Biogen has said it will be increasing minority participation in clinical trials, and Sutro Biopharma is working hard to increase diversity within company ranks.

The work to fight racism is showing up in clinical medicine as well. American Society of Clinical Oncology President Dr. Lori Pierce has made “Equity: Every Patient. Every Day. Everywhere” the theme of her Presidency. The American Medical Association has released a plan for ending structural racism not just within medicine, but also within the organization itself.

A pledge won’t transform an industry where BIPOC and Latinx employees are historically underrepresented, but it’s a start. We’re living in a time when many people, especially young people, expect corporations to do more than just maximize the bottom line.

I’m hopeful that these companies and organizations follow through on their words. But the industry could do one thing above all to attack racial disparities in healthcare.

It could make drugs more affordable. Especially for members of the BIPOC community.

As discussed here by Patients for Affordable Drugs Now, a patient advocacy group, the high price of prescription drugs helps to perpetuate systemic racism.

I want to applaud the industry for stepping up and taking pledges to do better to address racial inequities in hiring, career development, and representation in clinical trials. This is important work. But it’s simply not enough.

What’s going to have more impact: doubling the percentage of BIPOC employees at your company from three to six percent, or helping tens of millions of BIPOC people obtain the drugs you make?

Let’s not dream small. Why isn’t it possible to do both of these things?

BIPOC Communities are Marginalized by Biomedicine

There are many ways that Black people and other minority groups have been marginalized by the biomedical industry.

Here’s just a partial list of the disparities exposed and amplified by COVID-19 in the past year:

  1. Black people ages 35 to 44 were dying at nine times the rate of white people the same age from COVID-19.
  2. Neighborhoods that have higher COVID-19 hospitalization rates should have higher rates of COVID-19 testing, but if they’re majority Black neighborhoods, they don’t.
  3. Life expectancy in the U.S. fell in 2020 by the largest amount measured since WWII. Life expectancy for white people fell by a full year; for Black Americans it fell by 2.7 years.
  4. Racial bias was found in a major health care risk algorithm that is used for determining patient needs.
  5. Pulse oximeters used to measure blood oxygen levels, a quick and easy test to determine the severity of disease for a given patient, don’t work as accurately for many Black people.
  6. The number of kids being diagnosed with SARS-CoV-2 induced Multisystem Inflammatory Syndrome in Children (MIS-C) is growing in the U.S. Though MIS-C is rare, the majority of kids who get it are Black or Latino.
  7. In Palm Beach, Florida, COVID-19 vaccines intended for rural Black communities were instead given to wealthy white Floridians, and in general Blacks and other minority groups lag whites in getting the COVID-19 vaccine.
  8. In emergency departments at children’s hospitals in the U.S. from 2016-2019, Black children were 18% less likely and Hispanic children were 13% less likely than white children to receive X-rays, ultrasounds, CT scans, or MRIs.
Unfortunately, We’ve Seen This Movie Before

Some of the racial problems in healthcare are outside the control of the biopharma industry. But when the issue turns to race in biopharma, the industry tends to fall back on knee-jerk defenses that do nothing to solve longstanding racial inequities.

Biopharma has some movies I’ve had to watch far too many times. Three examples with comments:

  • Patients testifying in public that they can’t afford their drugs, or how unaffordability led to the death of a loved one.

The unaffordable price of drugs has been raised as an issue at least as far back as the Eisenhower administration and the Kefauver-Harris hearings that transformed the FDA in 1962. The industry managed to avoid price controls back then, and it’s beaten back every similar effort since. Our former President promised many times to lower drug prices. He broke that promise.

  • Drug prices can’t be cut because that would remove the incentive for innovation.

Venture capitalists are quick to point out that cutting prices would slow the development of new drugs. All of us would love to see a continuous stream of new and truly useful medicines. But what good are medicines, old or new, if patients can’t get them?

  • Listening to the CEOs of biopharma companies, healthcare insurers, and pharmacy benefit managers explain why they bear no responsibility for high drug prices, and why it’s always “the other guy’s fault.”

People are tired of these finger-pointing, blame-shifting exercises. Each of these special interest groups is there to protect itself, and each controls a small army of highly effective, well-paid lobbyists. Their combined forces would make a worthy opponent to those rampaging legions of Orcs in the Lord of the Rings movies.

The connections between these three industries are deliberately constructed to be opaque and hard for those on the outside to review and understand. For example, “rebate walls” have been set up between drug companies and PBMs. This term refers to contractual arrangements that control the placement of certain drugs on formularies that are used by most healthcare plans. Drug makers can offer higher rebates to the PBMs for any given medicine, or bundles of different medicines. This allows them to “wall off” other drug makers from getting favorable formulary placements for their drugs.

All of these groups should spend a lot less time offloading blame and focus instead on solving the problems of increasing access to medicines, reducing healthcare costs, and improving health outcomes. Mud slinging just promotes the growth of a swampy ecosystem of missed opportunities and wasted money. Everyone’s reputation gets bogged down in the muck and mire.

Reputation Resuscitated?

Life-saving COVID-19 vaccines were produced in record time, along with new and repurposed drugs for combating the pandemic. Many people are grateful for this work. Polls have shown that biopharma’s reputation is trending upward. That’s good news for the industry. Whether this will be sustained is an open question.

This positive movement in favor of biopharma is being counterbalanced in real-time by anti-vaccine forces, most of which are anti-pharma and anti-science. The anti-intellectualism and misinformation promulgated by these groups lingers like a bad cough, even as biomedicine successes continue to pile up.

Biopharma scandals continue, with large fines levied for all manner of offenses. Purdue Pharma is on the hook for $8B for driving the opioid crisis. Novartis agreed to pay $678M for making improper payments to doctors (i.e. kickbacks). Even after admitting this, Novartis was forced to walk back comments made by its chairman, who inaccurately insisted that the company had done no such thing.

Gaslighting is never a good look for an industry leader. Congressional testimony about drug pricing from the CEOs of AbbVie and Amgen was embarrassingly bad, wilting under the tough questioning of Rep. Katie Porter with her “whiteboard of truth.” This confirmed what many in the public already suspect, and which helps drive the anti-vaccine movement: the industry can’t be trusted.

Just as coal, oil, and gas companies need to change their business models because of the threat of global climate change, biopharma companies need to work much harder to ensure their medicines will be available to all those who need them.

It’s a reasonable request for an industry that continues to oppose state drug pricing boards, Canadian drug imports, and Medicare negotiations on drug prices.

The industry’s stance on those issues hasn’t changed in the past decade. But the industry can and must change.

The shifting position on racial diversity, equity, and inclusion is a sign that industry can do better. We need to hold it accountable. Let’s make sure the industry follows through on its promise by doing everything in its power to ensure that the poor, the disadvantaged, and BIPOC and Latinx folks gain access to the treatments and medicines that will enrich and prolong lives.

Stewart Lyman is a biopharma consultant based in Seattle.

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