Omicron shows why industry needs to update its priorities
New variant is first real test of biopharma’s adaptability against the virus
Effectively, the next pandemic is now here. The emergence of the Omicron variant of SARS-CoV-2 has given drug and vaccine developers a set of questions that will serve as an early test of how far the industry has come in pandemic preparedness, and whether biopharma’s COVID-19 countermeasure development strategies are sufficiently adaptable to meet the threat.
Most of the questions around the Omicron variant involve vaccine development, but one of the most important takeaways from the new variant’s emergence may be that small molecule antiviral development needs to be moved up the priority list.
With dozens of mutations — including more than 30 in the virus’ spike protein, which is targeted by approved vaccines — the Omicron variant first identified in South Africa less than a week ago presents one of the first real threats of a shift in the viral sequence that could render vaccines, and possibly therapies, less effective.
As with the start of a new pandemic, the unknowns dominate, in particular around how transmissible and how virulent Omicron will be, meaning companies are forced to make decisions in the dark.
The biggest near-term questions involve vaccines, which have taken priority over small molecule antivirals throughout the pandemic. Vaccines also face the biggest threat of resistance to this variant, given the location of the mutations.
The questions are how much the variant compromises efficacy, and what threshold should trigger rapidly prioritizing clinical development of a novel vaccine. With several vaccines approved and authorized, the main issue centers on timelines and whether a new vaccine can be created fast enough to counter this variant even as new variants may be on the verge of emerging elsewhere.
The “good” news, at least on the Omicron variant, is on the small molecule front, as fewer mutations appear to overlap with the small molecule binding regions.
However, nearly two years into the pandemic, only two novel targeted small molecules have made it to registration, and even before the Omicron variant emerged, there were concerns about manufacturing capacity.
Given the long development timelines for COVID-19 small molecule therapies and the potential sensitivity of available vaccines to viral evolution, the emergence of Omicron and other new variants underscores the need to better prioritize development of small molecules with viral mutagenesis in mind.
Vaccine next steps
The vaccine developers behind marketed mRNA vaccines for COVID-19 have both touted the modular benefits of the vaccine platforms, and their ability to be rapidly adapted to new viral sequences.
Omicron could be the first clinical test of that potential.
Creating a new mRNA vaccine involves swapping out the mRNA sequence in the manufacturing process; BioNTech SE (NASDAQ:BNTX) has said it can make a vaccine against a new variant ready for testing within six weeks.
While Moderna Inc. (NASDAQ:MRNA) and BioNTech, which is partnered with Pfizer Inc. (NYSE:PFE), have each developed vaccine candidates against other variants that have emerged since the start of the pandemic — and Moderna has tested several in the clinic — the question is what information the companies will want to see to accelerate development of those vaccines.
Factors affecting the decision are likely how contagious the virus is, the severity of symptoms it produces and how protective existing vaccines prove to be.
There’s broad hope that this time around there won’t be the same lag in gathering that information that slowed down the response to the Delta variant, which was first detected in India in February.
Though certain COVID-specific mAbs quickly proved less effective against Delta, clinical information on vaccine efficacy was slower to read out. Real-world evidence proving that the mRNA vaccines maintain efficacy against the Delta variant has been trickling in over the past few months.
Timing is crucial. Vaccine development, regulation and rollout need to be rapid enough to mitigate COVID-19’s spread while the target variant — or a variant with similar vaccine sensitivity — remains dominant in circulation.
Omicron will also test whether the regulatory experience and infrastructure created will expedite review and roll-out sufficiently, and whether the approach to vaccine distribution, in particular to low and middle-income countries, can shift to prioritize regions where the urgency is greatest.
Companies, and governments, will also need to weigh the benefits of continued booster doses against new vaccines designed for newer variants, and the questions then become: when should industry shift to a seasonal vaccine model, and how can it use directed mutagenesis to predict variants before they emerge?
Small molecule push
For small molecules, and vaccines in the longer term, a major question is how effectively companies are utilizing predictive mutagenesis data to guide development.
The combination of genomic surveillance and directed mutagenesis can give industry an edge over new variants, but it isn’t clear how much that information is feeding into development programs, or how actionable the information is given the breadth of potential mutation profiles.
Another question is how that technology can be optimized to advance pandemic preparedness, including preparedness for new SARS-CoV-2 variants.
Though the impact on efficacy of the two small molecule antivirals under FDA review, Paxlovid (PF-07321332) from Pfizer and molnupiravir from Ridgeback Biotherapeutics L.P. and Merck & Co. Inc. (NYSE:MRK), isn’t yet known, Omicron harbors just one mutation in the target proteins of each molecule — the protease for Paxlovid and the RNA polymerase for molnupiravir.
However, that doesn’t rule out mutations in future variants that impact therapeutic efficacy. It makes the case for development of therapies effective against a range of SARS-CoV-2 mutations. Strategies could include predictive modeling to guide drug design around potential emerging mutations, or creating a pipeline against diverse targets.
Whether the Omicron variant becomes a real threat to vaccine efficacy or only highlights that potential, it’s time for industry to shift its pandemic goals to prioritize preparedness for variants and future pandemics. Staying ahead of emerging variants in vaccine development and investing in novel small molecules that can bridge the gap when vaccine effectiveness wanes will be critical.