GEN: What would you say are the big-picture trends going into 2021?

Michael: Bioprocessing is moving towards single-use closed systems and connected processes, but the industry is conservative, and adoption is slow and steady. COVID-19 has kicked things further into gear, with considerable investment going to contract manufacturers who have built up extra capacity in vaccines and antibody production to address the pandemic. So there’s a question about what happens to that extra capacity afterwards.

GEN: What are the most interesting directions for cell therapy right now?

Michael: The big thing is that no one knows. I’d look out for signs of success in solid tumors, which is the big market cell therapy has to reach to go beyond being a niche for blood cancers. In the TIL area, look at lifileucel (LN-144) from Iovance Biotherapeutics, which is expecting to submit a BLA this year in metastatic melanoma. They’re the most advanced representative of that approach.

T cell receptor therapy (TCR-T) is another approach to look out for in solid tumors. GSK3377794 (GSK ‘794), an NY-ESO SPEAR T-cell therapy originally developed by Adaptimmune, was forecast to come out in 2022, and TCR2 have projects expected to come out in 2023. I’d watch those because they will give the first indications of the success of that approach clinically and commercially.

NK cells are also interesting because they’re naturally allogeneic and can be used for off-the-shelf rather than bespoke one-off (autologous) therapies like CAR-T. A big thing that’s held them back is the science of growing and scaling them, but that will get worked out.

GEN: What does this mean for manufacturing?

Michael: Cell therapies are still at a relatively early stage and are very heterogeneous in terms of what manufacturing process to use. It’s hard for suppliers to come up with a solution for everyone and so companies are beholden to one or two suppliers or the manufacturers need to put together their own, custom approaches.

Some suppliers are adapting equipment already used in conventional bioprocessing, where they know they have a market. Others are a bit more cautious, but willing to buy into technologies that seem promising in their own right.

One approach is selling a modular approach to manufacturing, but there are also companies offering all-in-one systems. Miltenyi is currently dominating that, but companies are tied into their system. That works well for academic institutions, who don’t have the expertise or labor for more industrial processes, but it’s difficult to reprogram for people who are in manufacturing for the long haul.

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While biopharma was dominated by COVID-19, which prompted a surge of research and business activity, the industry also saw developments that will position it for further growth even after the virus is brought under control.

The pandemic and other hot therapy areas drove venture capital (VC) financing to new heights, while propelling a new wave of mergers and acquisitions (M&A) activity as well as an increase in initial public offerings (IPOs). Clinical and commercial activity increased in traditional drug discovery as well as in cell therapy and gene therapy—the latter withstanding the deaths of four participants in two clinical trials. Investors warmed to emerging technologies offering the potential for new therapies, including genome editing and synthetic biology.

Below are seven biopharma-related trends cited by experts and others with a stake in the industry, as articulated in interviews with GEN, or in reports and other public statements.

1. COVID-19: Seeing the finish line

Hope for an eventual end to the COVID-19 pandemic was raised in November when positive Phase III vaccine data emerged from Pfizer and BioNTech, which promptly sought emergency authorization (EUA) for their BNT162b2 vaccine candidate. This hope was strengthened when Moderna reported progress about its mRNA-1273 vaccine candidate.

Other encouraging developments included the FDA’s approval of the first COVID-19 therapy, Gilead Sciences’ repositioned antiviral remdesivir (marketed as Veklury^®).

In December, two vaccines, Moderna’s mRNA-1273 and Pfizer/BioNTech’s BNT162b2, joined remdesivir in crossing the finish line of FDA approval. These vaccines will likely be joined by several others, including AZD1222 (AstraZeneca/University of Oxford), JNJ-78436735 (Johnson & Johnson’s Janssen Pharmaceutical), NVX-CoV2373 (Novavax), MRT5500 (Translate Bio and Sanofi), V591 (Merck & Co.), and an unnamed vaccine that is being developed by Sanofi and GlaxoSmithKline.

With the approval of multiple new vaccines, vaccination capacity is projected to grow nearly 150-fold, from 35 million people in the fourth quarter of this year to 5 billion people by the fourth quarter of 2021, according to a November 18 research note by Michael J. Yee, equity analyst with Jefferies, and three colleagues.

On the drug front, remdesivir will likely be joined on the market by two antibody therapies, bamlanivimab (Eli Lilly) and REGEN-COV2 (Regeneron Pharmaceuticals), for mild to moderate COVID-19. The FDA granted emergency use authorizations to Eli Lilly and to Regeneron in November, paving the way for their drugs’ eventual approvals. Also nearing approval is a combination therapy of remdesivir plus Eli Lilly’s Olumiant^® (baricitinib), indicated for hospitalized COVID-19 patients. It received an EUA in November.

2. Gene therapy: Big pharma, big deals

Big pharma firms have truly warmed to gene therapy to expand their pipelines in 2021 and beyond. Bayer agreed to acquire Asklepios BioPharmaceutical (AskBio) for up to $4 billion in October, followed two days later by Novartis purchasing ocular gene therapy developer Vedere Bio for up to $280 million. Roche agreed to spend up to $1.8 billion to use Dyno Therapeutics’ CapsidMap platform to develop next-generation adeno-associated virus (AAV) vectors for gene therapies for central nervous system diseases and liver-directed therapies.

Pfizer invested $60 million in Homology Medicines three days after Homology presented positive data from a Phase I/II trial (NCT03952156) for pheNIX, a gene therapy for adults with phenylketonuria (PKU). Among biotech giants, Biogen and Sangamo Therapeutics are developing and commercializing Sangamo gene regulation therapy candidates through a collaboration that could generate $2.7 billion-plus for Sangamo.

A continuing challenge in 2021 will be preventing tragedies arising from gene therapy clinical trials. In October, Lysogene disclosed that a five-year-old girl with mucopolysaccharidosis type IIIA (MPS IIIA) died in a Phase II/III trial (NCT03612869) designed to evaluate the company’s LYS-SAF302.

Between May and July, Audentes Therapeutics, which was acquired by Astellas Pharma for $3 billion in January 2020, acknowledged the deaths of three patients in a Phase I/II trial (NCT03199469) assessing its X-linked myotubular myopathy (XLMTM) candidate AT-132. The 3 were among 17 patients who received AT132 at the trial’s high dose of 3 × 10¹⁴ vg/kg. Audentes said all three patients who died showed notable features that included older age, heavier weight, and evidence of preexisting hepatobiliary disease.

“That is definitely a wake-up call for the field to really consider dose escalation more carefully, and to put much more emphasis on CMC [chemistry, manufacturing and control] than simply making a higher potency,” said Guangping Gao, PhD, the Penelope Booth Rockwell Professor in Biomedical Research at the University of Massachusetts Medical School, the director of the Horae Gene Therapy Center and Viral Vector Core, and the co-director of the Li Weibo Institute for Rare Diseases Research.

Despite the deaths, gene therapy did not see the disruption that followed the death of 17-year-old Jesse Gelsinger in 1999. According to the Alliance for Regenerative Medicine, gene therapy financing nearly tripled year over year, rising 178% to $3.5 billion in the third quarter of 2020. Between January and September 2020, financing jumped 114% to $12 billion.

The alliance recorded 373 gene therapy trials during the third quarter of 2020—up 4% from 359 in the second quarter but barely above the 370 reported in the third quarter of 2019. Of those trials, 115 were in Phase I, 223 in Phase II, and 32 in Phase III.

3. Genome editing: CRISPR and beyond

Genome editing showed in November that it, too, can spark big-money collaborations. Eli Lilly committed up to $2.7 billion toward using Precision BioSciences’ ARCUS^® genome editing platform to research and develop potential in vivo therapies for genetic disorders, starting with Duchenne muscular dystrophy. Bayer’s investment arm Leaps by Bayer co-led a $65 million Series A financing for Metagenomi, a developer of CRISPR-based gene editing systems for developing cell and gene therapies.

CRISPR Therapeutics and Vertex Pharmaceuticals continue to study CTX001, the CRISPR-Cas9 gene edited therapy that in June showed proof of concept in two patients with transfusion-dependent β-thalassemia, and effectiveness in another patient with sickle-cell disease, in two Phase I/II trials that are the first clinical studies of a gene editing candidate sponsored by U.S. companies.

A market report issued November 20 by the Business Research Company projected the global CRISPR technology market will grow from $1.65 billion this year to $2.57 billion by 2023, then leap to $6.7 billion by 2030.

That market is expected to grow faster once the ongoing legal wrangle is resolved over who invented CRISPR-Cas9. The bitter dispute is at the center of a second interference proceeding winding its way through the Patent Trial and Appeal Board (PTAB).

In September, the PTAB redeclared the interference by designating the Broad Institute of MIT and Harvard the senior party, and according junior party status to the Regents of the University of California, CRISPR Nobel Laureate Emmanuelle Charpentier, PhD, and the University of Vienna, collectively called CVC. The PTAB also held off immediately deciding which party offered the strongest evidence of being first to show CRISPR’s effectiveness in eukaryotic cells.

4. Financing: Impressive VC, M&A, and IPO activity

Capital flowed into biopharma companies, as shown by record-high VC investment. That trend is expected to continue in 2021, as are strong if not equally impressive gains in M&A activity, IPOs, and the broader stock market.

The quarterly MoneyTree Report, issued by PwC and CB Insights, showed a record-high $5.9 billion invested during the third quarter of 2020 in biopharma-related industries, dominated by $3.9 billion in 104 deals invested in biotech alone—more than double the $1.9 billion in 74 deals reported for the third quarter of 2019.

“It seems like the biotech and life sciences industry has been pretty much agnostic to COVID-19,” Ousmane Caba, partner, U.S. Pharmaceuticals and Life Sciences, PwC US, told GEN. “COVID hasn’t stopped IPOs, transactions, and M&A. The industry hasn’t been that impacted by the pandemic.”

Two factors have been driving financing in recent months, Caba said. One is the ability to apply data to biology. The third quarter’s largest VC recipient was Recursion, a digital biology company that completed a $239 million oversubscribed Series D financing led by Leaps by Bayer. The other is the longtime interest by drug developers and investors in fighting cancer, especially through technologies applicable to multiple forms of the disease.

Caba observed that the targeting of cancer helped drive a series of big-dollar M&A deals during 2020. Gilead Sciences in October completed its $21 billion acquisition of Immunomedics, which bolstered the buyer’s oncology portfolio with a first-in-class breast cancer treatment that received an accelerated approval from the FDA in April. Illumina plans to buy cancer blood test developer Grail for $8 billion, a deal set to close in 2021. Grail’s ability to apply data also made the company attractive, Caba said.

Also showing strength in 2020 was the market for first-time public stocks. During the first three quarters of 2020, biopharma firms raised a combined $9.32 billion in 51 IPOs, more than double the $3.6 billion garnered in 41 IPOs during the first three quarters of 2019, according to EvaluatePharma.

Overall, biotech stocks enjoyed healthy gains during 2020. As of November 20, the NASDAQ Biotechnology Index stood at $4,364.15, up 22% from $3,581.05 the same date a year ago.

“We do see pharma and biotech as undervalued as we approach the end of 2020,” said Karen Andersen, a healthcare strategist at Morningstar. “Overall, we’re seeing progress with several therapeutic areas. In neurology, even beyond aducanumab, we could see data in 2021–2022 to support new drugs against Huntington’s, amyotrophic lateral sclerosis, Parkinson’s, and Alzheimer’s.”

5. Drug development: Alzheimer’s and more

One of the most closely watched drug development stories in 2021 will be whether the FDA approves aducanumab, the Alzheimer’s disease candidate that Biogen is co-developing with Eisai. Aducanumab is being evaluated under priority review, with a target action date of March 7, 2021.

In November, aducanumab ran into an unexpected obstacle on the road to FDA approval after an advisory panel recommended against approving the drug. The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee balked at endorsing aducanumab. In March, Biogen halted EMERGE and ENGAGE, each a Phase III trial of the drug, after analyses indicated that the trials were unlikely to meet their primary endpoints. Then, in October, Biogen reported that a larger dataset for the EMERGE trial had become available, and that analysis of this dataset had showed a significant reduction in clinical decline. Biogen also indicated that in the ENGAGE trial, data from a subset of patients supported the new conclusions about the EMERGE trial.

“We think aducanumab will get a complete response letter in early 2021 requesting another large trial ahead of approval. We assume a 40% probability of approval in 2024,” Andersen said. “If Biogen gets a complete response letter, they will have to decide if they want to continue investing in aducanumab, or focus efforts on a similar antibody, BAN2401, that is already in a couple of Phase III studies with partner Eisai.”

Andersen added that aducanumab will either lead to more attention and higher valuations for Alzheimer’s programs, such as the programs at Roche and Eli Lilly, or dampen the enthusiasm for therapies that are based on clearing amyloid plaques: “Either way, we expect continued investment in other mechanisms of action, especially tau, and other modalities that can better cross the blood-brain barrier, like Denali’s small molecule inhibitors of leucine-rich repeat kinase 2 (licensed by Biogen), or RNA-based therapies, like those of Ionis Pharmaceuticals partnered with Biogen.”

According to Andersen, drug developers also continue to see progress in oncology. She cited antibody-drug conjugates, like those of Seagen (formerly Seattle Genetics), and two therapies with breast cancer indications—AstraZeneca’s Enhertu^® (fam-trastuzumab deruxtecan-nxki) and Trodelvy (sacituzumab govitecan-hziy), which Gilead Sciences will inherit when it finishes acquiring Immunomedics. She added, “We expect more combination data with PD-1/PD-L1 antibodies for multiple bispecific antibody programs and other antibodies as well.”

6. Cell therapy: Buyers large and small

Developers are expected to extend last year’s cell therapy developments into 2021. Last November, PerkinElmer agreed to acquire Horizon Discovery Group for approximately $383 million, in a deal intended to add gene editing and gene modulation tools to the buyer’s portfolio of automated life sciences discovery and applied genomics solutions. Sanofi in November shelled out about $364 million to acquire Kiadis Pharma, a developer of natural killer cell therapies. Most of these therapies are focused on cancer, but one therapy in preclinical development is targeting COVID-19.

Two pharma giants completed facilities focused on cell therapy development. In September, Takeda Pharmaceutical opened a new R&D cell therapy manufacturing facility within its research headquarters in Boston. In October, Astellas Pharma opened a $120 million facility to be occupied by the Astellas Institute for Regenerative Medicine (AIRM). The new facility, which is located in Westborough, MA, is to focus on cell therapy manufacturing as much as on R&D.

Cell therapy financing grew at an impressive rate. According to the Alliance for Regenerative Medicine, cell therapy financing as of November 2020 reached $3 billion in the third quarter and $11 billion year to date, up 97% and 242%, respectively. The number of Phase I trials assessing cell therapies increased from 41 to 50 (for the first three quarters of 2019 and for the first three quarters of 2020, respectively) but dipped in Phases II and III. Overall, the number of clinical trials decreased from 218 to 202 trials as of the third quarter.

7. Synthetic biology: In the money

SynBioBeta recently shared some numbers illustrating the increasing allure of synthetic biology to investors. During the first half of 2020, total financing in the sector reached $3.041 billion (among 56 companies). During the first half of 2019, it was $1.9 billion (among 65 companies). The largest financing, $700 million, was raised by Sana Biotechnology, a developer of therapies that are based on engineering cells.

The synthetic biology money train continued into the second half. In September, Zymergen raised $300 million intended to propel its expansion into the $3 trillion chemical and materials industries; accelerate the manufacture of its biofabricated Hyaline film for electronics applications; and commercialize additional products with applications in electronics, agriculture, consumer care, and healthcare.

“The takeaway: coronavirus is not hampering the estimated $4 trillion bioeconomy being driven by synthetic biology,” SynBioBeta founder John Cumbers, PhD, commented recently in Forbes.

If anything, COVID-19 is helping to drive synthetic biology activity and will continue to do so in 2021. Ginkgo Bioworks raised $70 million in May toward developing large-scale testing infrastructure. In July, the company announced an approximately $40 million award from the NIH Rapid Acceleration of Diagnostics Advanced Technology Platforms (RADx-ATP) program to scale its automated technology for SARS-CoV-2 testing using next-generation sequencing.

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Since the birth of the biotechnology industry in the late 1970s, many transformational technologies and new treatments have been introduced, improving medical care and benefitting patients. And in many areas of medicine, exciting progress continues. However, there are many areas where standard of care is fundamentally limited, and significant challenges remain. So, it’s natural to ask, what advances will the next decade bring? How will the landscape evolve in light of key healthcare and technology trends?

One way existing challenges could be addressed is through the development of innovative technologies and treatments that could help restore health more effectively and efficiently, shorten hospital stays, lessen dependence on supportive care, and reduce the need for home healthcare or nonclinical institutional care facilities.

Many areas of clinical medicine could be transformed by advances in regenerative medicine, a field that includes cell therapy, gene therapy, gene modified cell therapy, and tissue engineering. Over the past few years, this field has started to come of age. Over the next decade, it will, many believe, achieve its long-anticipated potential and begin to fundamentally reshape clinical medicine as we know it.

Healthcare systems stressed by aging populations

Where is the field likely headed in the next few years? What are some of the key trends in healthcare that regenerative medicine technology might be helpful in addressing?

From a therapeutic standpoint, clinical trials evaluating regenerative medicine technologies and treatments have considered a broad range of disease indications and clinical challenges. These include cancer; neurological indications; cardiovascular disease; inflammatory and immune conditions; endocrine, metabolic, and genetic disorders; musculoskeletal and opthalmological conditions; and a host of others. The therapeutic indications under evaluation reveal the enormous scope regenerative medicine could achieve.

There are two major healthcare trends that these innovative technologies may help to address. One is the continued expansion of the elderly segment of the global population. The other is the corresponding impact on healthcare systems. By the year 2030, the entire population cohort of “baby boomers,” defined as those individuals born between 1945 and 1965, will all be 65 years of age or older.

According to the American Association of Medical Colleges (AAMC), between 2018 and 2033, the portion of the U.S. population under the age of 18 will increase by approximately 3.9%, while during the same period, the population 65 years of age or older will grow by more than 45%—to more than 77 million people. By 2034, the U.S. Census Bureau predicts that that for the first time in our nation’s history, people over the age of 65 will outnumber those under the age of 18.

This unprecedented demographic shift matters because it will have a profound impact on healthcare resource utilization here in the United States. (Similar shifts, and consequences, are expected elsewhere around the world.) As the population gets older and as we collectively become more susceptible to age-associated health problems, we face another serious challenge—a growing shortage of physicians and nurses. By 2033, the AAMC estimates, there will be a shortage of between 54,000 and 139,000 physicians across all specialties.

According to the American Nurses Association (ANA), there will be a national shortage of more than 100,000 registered nurses by 2022. The ANA also estimates that the number of nurses needed in the United States will grow from 2.8 million in 2018 to 3.6 million in 2030. The prospect of an expanding elderly population, the corresponding increase in demand for healthcare resources, and an escalating shortage of qualified physicians and nurses are discomforting to say the least.

According to the Alliance for Regenerative Medicine (ARM), currently there are approximately 1,000 companies around the globe that are developing regenerative medicine treatments and technologies, with most of them located here in the United States. Furthermore, there are now more than 1,000 clinical trials currently being run, with 587 of them in Phase II and 97 of them in Phase III. Many of these programs are focused on serious diseases and conditions that will have an increasing impact in an aging society, as well as other areas of unmet medical need.

Developments in regenerative medicine

Age-associated health problems that affect us individually and collectively may be alleviated by regenerative medicine. At present, the continued growth and evolution of regenerative medicine seems assured by five key trends.

1. The number of late-stage clinical trials will continue to rise, and the number of approved therapies will meaningfully increase.

Phase II trials are notorious for being the riskiest phase of development—with the greatest amount of attrition. With nearly 600 Phase II trials ongoing, we are likely to see both some exciting advances and some frustrating failures in the next few years.

The successes will beget additional capital investment, growth, and development—and the failures will demand critical reassessment. Some failures will be due to unexpected safety issues and/or a lack of efficacy, some prompting a discontinuation of programs, and others will be due to clinical trial design issues that might be addressed through more effective inclusion/exclusion criteria, or utilization of clinical endpoints that more appropriately evaluate and ultimately demonstrate therapeutic benefit.

Given the nearly 600 Phase II programs, there will likely be several hundred programs that advance to Phase III development. Given the approximately 100 Phase III programs now underway, we might expect dozens of these to be successful and clinically validated, and to obtain subsequent regulatory approval.

2. There will be a shift away from more expensive, highly personalized treatment approaches, toward more scalable and standardized “off the shelf” treatment approaches.

The advent of chimeric antigen receptor (CAR) T-cell technology to treat patients with refractory hematological malignancies is in many ways illustrative of both the challenges and opportunities facing the sector as a whole. Unquestionably, the technology represents treatment breakthroughs—but while demonstrating promising effectiveness, the initial approaches using gene-modified autologous cells face scalability challenges and are prohibitively expensive.

As a result, we already see dozens of companies and programs that are focused on next-generation approaches applying the same concepts using allogeneic platforms that could be administered “off the shelf,” and would be far more scalable and cost effective. Manufacturing scalability and consistency will improve—but only for those technology platforms that permit it.

3. Mergers and acquisitions in the sector will increase appreciably.

In the past five years, major biopharmaceutical companies have recognized the enormous potential of the regenerative medicine sector. These companies anticipate that the sector will have an impact in disease indications and clinical situations where there is unmet medical need due to limitations in standard of care, and where traditional pharmaceuticals or biotechnology products may not provide effective or durable relief. Large companies also have a relentless need to grow and rejuvenate their pipelines, and when promising approaches emerge, many of these will likely be acquired by larger established companies with strong channels to market.

4. Supply chain technologies and distribution capabilities will accommodate novel therapeutic modalities.

Traditional pharmaceutical supply chain and logistics practices are not well suited for advanced biologics—regenerative medicine technology generally requires specialized capabilities including cold chain or cryogenic product handing, storage, and distribution. Companies that solve these challenges will have stronger and more efficient channels to market. Those companies that wait for someone else to solve these issues will either sacrifice value or be commercially disadvantaged.

5. Coding, coverage, and reimbursement models will accommodate innovative regenerative medicine products and emphasize value.

Regenerative medicine treatment approaches have the potential to provide durable relief and, in some cases, even curative outcomes. However, if such approaches utilize highly personalized therapies or if they address small patient populations, reimbursement levels may have to be very high to justify the significant investments involved in developing such treatments.

Traditional coding, coverage, and payment systems are not generally designed to facilitate the rapid adoption or coverage of such approaches—even when they have the potential to transform medical care and outcomes for patients. But given the stakes, patients and their families will demand access to more effective treatments, and third-party payers will adapt to accommodate them. Payors and innovators will have to work together to holistically evaluate the value of these medicines, as well as to pay for them, to accommodate patient demand.

Conclusion

Limitations in standard of care and unmet clinical needs, as well as the corresponding desires for better outcomes and improved quality of life by patients and their families, will continue to drive medical innovation. Such advancements are possible only if investment fuels the innovation and sensible policies are implemented to help enable the efficient development of new medicines. There are serious challenges and obstacles ahead, but in many ways, the future of regenerative medicine couldn’t be brighter.

Gil Van Bokkelen, PhD, is chairman and CEO, of Athersys.

To help us preview the future, we asked opinion leaders, all from outstanding technology companies, to discuss a range of new initiatives. The full list of articles is below.

Leroy Hood: Reflections on a Legendary Career
Uncharted Territory: Top Challenges Facing Gene Therapy Development
Envisioning Future Trends in Regenerative Medicine
Engineering Biology—Accelerating Transition
Bioprocessing in a Post-COVID-19 World
Sustainability and the Synthetic Biology Revolution
Sowing the Seeds of Agricultural Biotechnology
Neuroscience Widens Its Investigations of Disease Mechanisms

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