Oncology R&D Outlook 2020: The Ongoing Impact of COVID-19
By Dennis Chang, Dan Holohan, Edouard Mullarky, and Rachit Neupane
COVID-19 has escalated into a global pandemic with shocking speed and poses an unprecedented challenge for all facets of society. Oncology research and development has been no exception. Necessary measures to slow the spread of the disease (e.g. travel restrictions, quarantines, and social distancing), or “flatten the curve”1,2 have already had a disruptive effect on drug development that will be felt for months, and possibly years, to come. As serious as these disruptions are to the development of new cancer therapies, they pale in comparison to the potential impact of failing to flatten the curve.
China and Italy
Due to a number of reforms and policies3, China has been maturing into one of the top pharmaceutical markets in the world. Its prominence can be seen in the country’s ability to achieve steep pricing discounts (an average of ~60%) from drug manufacturers3. China is also an emerging source of biopharma innovation. In oncology, important new therapies developed by Chinese companies include: zanubrutinib (Brukinsa) [Beigene], a next-generation BTK inhibitor approved by the FDA in November 2019 for mantle cell lymphoma; LCAR-B38M (a.k.a. JNJ-68284528) [Legend Biotech in partnership with Janssen] a BCMA-targeted CAR-T cell therapy with compelling efficacy in multiple myeloma4; and many, many more. China also has one of the largest immuno-oncology (IO) pipelines in the world, second only to the US5.
Recently, however, much of the Chinese biopharma sector—indeed much of the Chinese economy—has been brought to an abrupt halt due to historic quarantine measures and a desperate need to prioritize managing tens of thousands of confirmed cases of COVID-196,7. Fortunately, draconian quarantine measures have been successful in slowing the spread of the disease, and are starting to be relaxed, which may allow at least a partial revival of R&D activities. However, the pandemic is far from over: thousands in China continue to suffer from the illness. The contagion continues to spread globally, and it remains unknown whether immunity to COVID-19 is persistent or if reinfection is possible8. A continued or renewed state of travel and work restriction remains a possibility9.
Italy was slower to enforce quarantine measures, and even with a nationwide quarantine now in place, it is suffering a higher per capita rate of infection and mortality, and as a result of a much more severe burden on the healthcare system10,11. Italy is a major contributor to cancer research and cancer care, with 40 ESMO Designated Centres of Integrated Oncology & Palliative Care across the country12, but lockdown measures have closed many cancer research labs13,14. Cancer clinical care has been reorganized to redirect resources to COVID-19 management and reduce risk15, but delays in treatment, monitoring, and testing have been inevitable16. These measures are still in full force as of print.
In many other countries, including the US, the epidemic is still in the early stages, and the social distancing measures remain weaker, but the impact is still being felt.
Disruption of research activities
In the US, the partial closures of university campuses and associated laboratories have curtailed a vast array of basic science activities and clinical studies. For example, the Fred Hutchinson Cancer Research Center in Seattle, WA (one of the COVID-19 hotspots in the US) has minimized its on-site activities, shifting as much as possible to remote work17. Similar measures have been implemented across Boston-area research institutions18.
A survey conducted March 12-13 of 170 US clinical trial sites found that 39% of sites expected less patient enrollment in new trials, and 25% expected reduced rates of continuation of ongoing trials19. Notably, the COVID-19 incidence and social distancing measures have increased significantly since the survey was conducted. FDA has issued new guidance on conducting clinical trials to try to mitigate the impact, allowing for protocol amendments and alternative assessment methods20, but the pace of research will certainly be slower for months to come. Eli Lilly has already announced broad curtailing of R&D activities, pausing new study starts and enrollment across clinical programs21.
Delays in communication of research results and medical education
Oncology conference cancellations or postponements thus far include the AACR Annual Meeting22, the Society of Gynecologic Oncology (SGO) Annual Meeting23, and the NCCN Annual Conference24. More disruptions of major meetings are expected to follow.
Disruption of regulatory agency activities
FDA has announced the suspension of some of its regular activities including foreign manufacturing site inspections. This is expected to delay approval timelines of new therapies25.
Reduced investment and funding of biopharma startups
The world is looking to biopharma and biomedical research centers to develop vaccines and therapeutics for COVID-19, and the sector is rising to the challenge: over 100 clinical trials were already planned or underway less than 3 months after the new virus was recognized26. While the impact of COVID-19 is not yet clear for oncology-focused biopharma startups, societal disruptions and the economic slowdown are expected to take a toll eventually; investment will contract, and fewer startups may be founded or successfully traverse the proverbial “valley of death”27.
Potential Future Impact
If the pandemic is not mitigated, models estimate over two million Americans will die and millions more will require intensive care. Even with mitigation, the death toll may still be in the hundreds of thousands28. Many of the direct casualties will be our cancer patients, who are more vulnerable due to respiratory comorbidities and weakened immunity. A study of Chinese patients found that COVID-19 infection and mortality rates are significantly higher among cancer patients than in the general population29.
Health care workers also have a far higher risk of exposure and infection. The rate of COVID-19 infection among health care workers in the Lombardy region of Italy has been approximately 20%12. Biotech innovators are not immune either, as demonstrated by the infections of many industry leaders, including dozens of Biogen executives who attended a healthcare conference30.
Further deaths will arise from an overwhelmed healthcare system. Cancer surgery and other clinical treatment is being delayed due to the reorganization of schedules and, in some cases, infection-related closures of clinics31. A flood of COVID-19 cases would deplete hospital resources, putting at risk not only COVID-19 patients, but also those requiring ICU and other Emergency Department services.
The R&D disruptions associated with social distancing are generally reversible, but the consequences of a failure to flatten the curve will be irrevocable.
The Light at the End
As dire as it is today, the COVID-19 pandemic will eventually end. The Spanish Flu pandemic of 1918 was devastating but ran its course in about one year32. There is no guarantee that the coronavirus timeline will be similar, but there is reason to be hopeful, as our biomedical know-how and technologies are now vastly superior than a century ago, as is our capability to share information and collaborate at a distance. Timelines may be delayed by the pandemic, but transformative treatments for cancer will continue to emerge. This remains an energizing, hopeful time for oncology; some of the innovations we anticipate over the next year or two include:
- The next wave of anti-PD1 combinations
- Anti-PD1/PD-L1 immunotherapy is arguably the greatest oncology breakthrough of the last decade; combining anti-PD1 with another IO agent has been hypothesized to be even more powerful, but many such combinations have been unsuccessful. In 2020, new contenders will take steps forward. For example, Nektar may report new data for bempegaldesleukin (NKTR-214, an IL-2 agonist) plus pembrolizumab (Keytruda) [Merck] in NSCLC and start multiple new phase 3 trials in combination with nivolumab (Opdivo) [BMS]33
- Three combinations of anti-PD1 + kinase targeted therapy (TT) were approved in 2019 based on compelling efficacy34. In the 2020–2021 timeframe, we look forward to additional phase 3 readouts of IO+TT, including pembrolizumab + lenvatinib (Keytruda + Lenvima) in RCC, and spartalizumab (anti-PD1) + dabrafenib (Tafinlar, a BRAF inhibitor) + trametinib (Mekinist, a MEK inhibitor) [Novartis] in BRAF-mutant melanoma26
- A rising wave of antibody-drug conjugates
- 2019 saw the approvals of trastuzumab deruxtecan (Enhertu) [AstraZeneca/Daiichi Sankyo] for HER2-positive breast cancer and enfortumab vedotin (Padcev) [Seattle Genetics/Astellas] for urothelial cancer, two ADCs with exciting efficacy in their respective indications for patients after failure of prior therapies34. In 2020, we expect to see more ADC approvals including belantamab mafodotin [GSK], a BCMA-targeted ADC for multiple myeloma35, and sacituzumab govitecan [Immunomedics], a Trop2-targeted ADC for triple-negative breast cancer36, as well as continued data readouts for a growing pipeline
- New data and milestones for CAR-T therapies and bispecific
- 2020 may also see a major milestone for BCMA-targeted CAR-T cell therapy for multiple myeloma: BMS/Celgene and bluebird bio expect to submit a BLA for bb21217 this year37. Key competitor LCAR-B38M/ JNJ-68284528 [Legend Biotech/Janssen] is expected to complete its pivotal CARTITUDE-1 trial in 202126
- Companies using gene editing to create allogeneic “universal” CAR-T therapies will have data readouts in 2020 for early phase trials, including Allogene38, CRISPR Therapeutics39, Precision Bioscience26, and Celyad26
- Bispecific antibodies that engage T cells against a cancer marker are often pitched as competitors to CAR-T therapy: they may have lower efficacy but offer off-the-shelf administration and lower cost. For example, AMV564, a CD33-targeted bispecific from Amphivena, is expected to complete a phase 1 trial in MDS this year, and AMG 420, a BCMA bispecific from Amgen, is expected to complete its phase 2 in myeloma in 202126
- Further progress targeting KRAS
- Preliminary efficacy data for KRAS G12C inhibitors, AMG 510 [Amgen] and MRTX849 [Mirati] generated excitement in 2019 that KRAS may finally become “druggable”. New readouts in 2020 may include additional phase 1/2 data for MRTX849 and first-in-human data for BI 1701963 [Boehringer Ingelheim], a first-in-class inhibitor of the KRAS activator protein SOS126. We also expect to see the initiation of combination studies including combinations of SHP2 inhibitors with KRAS G12C inhibitors: Revolution Medicines’ RMC-4630 in collaboration with AMG 510, and Novartis’s TNO155 in combination with MRTX84940