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The Evolution of CRISPR Technology from Editing to Diagnostics

This year marks the 10-year anniversary of when CRISPR-Cas9 gene editing was first revealed to the world. Much has happened since then, including wide…

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This year marks the 10-year anniversary of when CRISPR-Cas9 gene editing was first revealed to the world. Much has happened since then, including wide rollout in many sectors, development of CRISPR-based therapeutics and the discovery that the technology can also be used to develop highly accurate and affordable diagnostics.

The discovery that using CRISPR plus a guide enzyme known as Cas9 could allow targeted gene editing was published in a paper in Science in June 2012 authored by University of California, Berkeley, biochemist Jennifer Doudna and microbiologist Emmanuelle Charpentier, then based at Umeå University, Sweden, along with colleagues.

At a similar time, a molecular biologist at the Broad Institute, Feng Zhang, and his team were also working on developing CRISPR-Cas9 gene editing technology. While the Berkeley team filed for a patent for the technology a few months before Zhang and colleagues, a long-running argument and patent dispute continues between the two groups about who invented the technology first.

Clustered regularly-interspaced short palindromic repeats (CRISPR) are a family of DNA sequences found in bacteria and archaea. Derived from fragments of bacteria-eating viruses called phages, the previously infected microbes use these sequences to detect and destroy DNA from new phage virus attacks. With the help of suitable guide enzymes, such as Cas9, this bacterial ability can be harnessed to carry out precise genetic edits in many different genomes.

Since the initial discovery, use of CRISPR gene editing technology has exploded around the world for many different uses both in and out of the clinic, in academia, and in industry. Doudna and Charpentier, as well as Lithuanian CRISPR pioneer Virginijus Siksnys, were recognized for their discovery and awarded the Kavli Prize in Nanoscience in 2018, followed by the Nobel Prize in Chemistry in 2020  for Doudna and Charpentier.

As well as ever expanding uses, including genome editing, gene therapy, epigenetic modulation, and many others, the technology itself is also evolving. No longer limited to just the Cas9 enzyme as a guide, many others have been developed and are now being used for different purposes. Discovered in 2015 and 2016, respectively, Cas12 binds strongly to a DNA target, remains bound and then non-discriminately cleaves single stranded DNA in the vicinity, whereas Cas13 binds an RNA target before similarly cleaving nearby single stranded RNA.

“When some of these enzymes were first discovered, this collateral cleavage activity was a bit of a concern. But it turns out, you can harness that for diagnostic purposes,” Princeton University associate professor and group leader Cameron Myhrvold, who has experience working in this area, told Inside Precision Medicine.

The discovery of these new Cas enzymes really catalyzed researchers to investigate how CRISPR technology could be used in diagnostics and over the last few years several biotech companies have been set up to explore this potential. COVID-19 has further spurred on the use of CRISPR in diagnostics. However, it remains to be seen whether and in what form the current consumer, investor and industry interest will continue once the pandemic is officially over.

Exploiting the Power of New Cas Enzymes

Janice Chen CTO
Mammoth Biosciences

One of the first companies to explore the potential of CRISPR technology for diagnostic applications was Mammoth Biosciences. Founded in 2017, by Doudna and two of her graduating PhD students Janice Chen and Lucas Harrington, as well as Trevor Martin from Stanford University, the company was set up, at least initially, to explore how Cas12 and Cas13 could be used in diagnostics. “A lot of the work that was foundational to starting Mammoth was done in the lab of my professor, Jennifer Doudna, at UC Berkeley, together with one of my co-founders, Lucas Harrington, and our colleagues there,” explained, current CTO, Chen in an interview. “One of the really unexpected findings was that you could use CRISPR, not just for gene editing, but also for gene detection. That was a new opportunity in the field and opened up this opportunity for molecular detection using CRISPR.”

The company has developed a platform called DNA endonuclease-targeted CRISPR trans reporter (DETECTR) using Cas12 (previously known as Cpf1). The CRISPR nucleases are programmed to find a specific sequence in the DNA, using a guide RNA. When the sequence is found, Cas12 also cuts a single stranded fluorescent reporter sequence in the reaction, which signals that the pathogen of interest has been found. The system was tested on two similar types of human papilloma virus (HPV), HPV16 and HPV18, and was able to distinguish between them within an hour. While the company has diversified since 2017 and is now also developing therapeutics, use of CRISPR for diagnostic purposes is still one of its key areas.

Adriana Dantas Lemberg
Adriana Dantas Lemberg, VP Product Management in Diagnostics, Mammoth Biosciences

“What we know is that we can do much higher multiplexing than what we see in currently available commercial products,” Mammoth VP of Product Management in Diagnostics Adriana Dantas Lemberg told Inside Precision Medicine.

“CRISPR is cleaner, more elegant and less prone to interference than the sample preparation that is required on any PCR reaction. So, I think that’s the greatest advantage that we’re going to see.”

The second big player in the field of CRISPR diagnostics is Sherlock Biosciences. The company was set up in 2019 to commercialize earlier findings from Feng Zhang and colleagues at the Broad Institute, showing the potential of CRISPR-Cas13 (previously known as C2c2) for detection of RNA sequences. Jim Collins is a professor at MIT and a core founding faculty member of the Wyss Institute at Harvard University. He is also a co-founder of Sherlock, along with Zhang, David Walt, another Harvard professor, and a number of other researchers.

Jim Collins
Jim Collins, Professor, Wyss Institute at Harvard University

“I think it goes back to the spring of 2016. My team had developed a paper-based diagnostic for Zika… we showed you could use CRISPR-Cas9 to differentiate between different strains,” explained Collins. “When that paper came out, Feng Zhang, my colleague, here at MIT and the Broad, reached out and shared that his team was working on a different CRISPR enzyme, Cas13, and asked if I would be interested in collaborating with his group on potentially using this enzyme to create a new diagnostic platform.”

This marked the start of Sherlock, named after its platform – Specific High Sensitivity Enzymatic Reporter UnLOCKING (SHERLOCK). Similar to DETECTR, the platform works by targeting RNA sequences of interest and cleaving and activating a fluorescent reporter sequence to indicate a positive result.

Bryan Dechairo
Bryan Dechairo, VP of Clinical Development, Myriad Genetics

Unlike Mammoth the company has remained focused on diagnostics, but is now trying to make its products even easier and more cost effective to use by increasing its focus on point of care, as opposed to laboratory-based testing, and has a new fast test in development. “It works isothermally at ambient temperatures and therefore requires no heat, no electricity whatsoever. That technology can detect from sample to answer in just under an hour,” explained new CEO, Bryan Dechairo, who moved to the company from his position as Executive Vice President of Clinical Development at Myriad Genetics last year.

Sherlock had started work on diagnostics for sexually transmitted infections before the pandemic started, specifically in the areas of chlamydia and gonorrhea. “We have now continued those programs and are moving them forward, especially now that our chemistries really meet the market demand for speed, accuracy and costs,” says Dechairo.

Mammoth Biosciences Headquarters San Francisco, CA
Mammoth Biosciences headquarters in San Francisco, CA

Combining Transistors With CRISPR

Making use of new Cas enzymes is not the only way to create a CRISPR-based diagnostic tool. Kiana Aran, an associate professor and group leader at the Keck Graduate Institute in California, is also CSO at Cardea Bio. Previously named Nanomedical Diagnostics, the company was set up in 2013 to develop electrical biosensors using graphene.

After joining the Keck Institute in 2017, Aran also began work with what is now Cardea Bio to produce the company’s Biosignal Processing Unit (BPU). This is a next generation electrical transistor that uses graphene instead of silicon and can pick up a variety of biological signals. “Graphene is much more biology friendly,” explains Aran, “biology doesn’t impact it and its super sensitive.”

Dr. Kiana Aran
Dr. Kiana Aran
Associate Professor
Keck Graduate Institute, California

The BPU can be adapted to host a number of different detector molecules including CRISPR. As described in a 2019 Nature Biomedical Engineering publication, Aran and colleagues added immobilized and catalytically deactivated CRISPR-Cas9 on the chip allowing targeting of specific genetic sequences.

The first proof of concept for the technology involved testing DNA samples with two distinct deletion mutations from individuals with Duchenne muscular dystrophy. Within 15 minutes the chip identified samples with the correct target sequence, without the need for a DNA amplification step.

However, the Cas9 enzyme they used initially was not able to pick up smaller mutations. “In 2021, we worked with Dr Virginijus Siksnys who was one of the pioneers in CRISPR… He’s a close collaborator of mine,” said Aran. Siksnys introduced Aran to a different Cas9 variant that was more sensitive to single point mutations and was able to pick up those causative for sickle cell disease and amyotrophic lateral sclerosis (ALS).

“They have a library of different Cas enzymes, and each of them have a different functionality. Some can operate at higher temperature, some are more sensitive to single point mutations, and a whole wide range of other characteristics. He helped us select an enzyme that was best for our application.”

Cardea chipThese are just some possible uses for the technology, explains Aran, who adds that she and her colleagues hope it will be useful in fields such as cancer. “For liquid biopsy, if you’re detecting free circulating DNA or reciprocating RNA, you’re not just interested in detecting ‘yes’ or ‘no’, you’re interested in testing how much of it you have so you can see if therapy has been effective.”

The Cardea technology also has other uses linked with CRISPR, as it can test how effective different parts of the reaction are with different complexes and enzyme combinations. Just last month, Cardea launched a spin off company called CRISPR-QC, which plans to focus on helping researchers and companies using CRISPR technology, for example, those developing medical gene editing therapies, to improve and monitor the quality of their experiments.

The COVID Effect

Since 2020 the world has changed. We have all gone through a global pandemic and the importance of vaccines, therapeutics and effective diagnostics has never been clearer. Diagnostics historically has been a difficult business to master. “We know that diagnostics drive 70% of the decision making in clinical settings. But only 2% of the total budget and healthcare systems are spent in diagnostics,” explained Dantas Lemberg.

However, since the beginning of the pandemic, different types of diagnostic tests such as PCR, RT-LAMP (loop-mediated isothermal amplification) and antigen tests have become a common discussion topic over the dinner table. Like many companies in the life science space, companies with a focus on diagnostics or related areas were quick to begin developing tests for SARS-CoV-2. Sherlock achieved the first ever FDA approval, albeit an Emergency Use Authorization (EUA) rather than a standard approval, for CRISPR in a medical setting with its rapid CRISPR SARS-CoV-2 test kit in May 2020. Earlier this year, Mammoth also achieved an EUA for its high-throughput SARS-CoV-2 test that combines CRISPR technology with laboratory automation for diagnostic testing.

Sid Shenai
Sid Shenai, Proof Diagnostics CEO & co-founder, Sherlock Biosciences

Many new startups also decided to try their luck at developing COVID vaccines, drugs and diagnostics. One such company is Proof Diagnostics. In early 2020, Feng Zhang, Jonathan Gootenberg and Omar Abudayyeh, all of whom are also Sherlock founders, decided to launch a new company to commercialize and build a new type of point of care, easy to use CRISPR diagnostic based on their SHERLOCK testing in one pot (STOP) assay.

“What’s been a silver lining in this really terrible two and a half years is you’ve seen a lot more investment from the public sector and from the private sector go into the space,” says Proof CEO, Sid Shenai. “Five years ago, not a whole lot of investors were very focused on diagnostics.”

Cameron Myhrvold
Cameron Myhrvold
Broad Institute Professor
Pardis Sabeti

Cameron Myhrvold has also been applying his expertise to developing CRISPR-based COVID tests over the last few years, using the knowledge he gained as a PhD student in the lab of virologist and Broad Institute professor Pardis Sabeti (also a Sherlock co-founder). Myhrvold has worked with Cas13 since becoming a postdoc and now has his own lab at Princeton with a focus on using CRISPR to study viral and host RNA. Before starting at Princeton, Myhrvold worked with Sabeti and team to help develop a technique to test for multiple pathogens at the same time called Combinatorial Arrayed Reactions for Multiplexed Evaluation of Nucleic acids (CARMEN). By combining CARMEN with Cas13, Myhrvold and colleagues were able to test more than 4500 targets on a single array.

During the pandemic, Myhrvold and his team adapted the earlier CARMEN work to help test for different strains of SARS-CoV-2. Microfluidic (m)CARMEN, combines CRISPR-based diagnostics and microfluidics and can test for up to 21 viruses including variants of SARS-CoV-2. “The work has been translated a lot faster than I could ever have imagined,” says Myhrvold.

“Omicron has a unique combination of mutations that differentiated it from Delta and from all of the previous variants. When the Omicron variant started spreading across Massachusetts, our assay, even though we didn’t design it for Omicron, was ready to go. We were able to use it, both in some colleges in the Boston area, as well as in partnership with the Department of Public Health in Massachusetts, in order to track the spread over time.”

Predicting the Future

Molecular diagnostics was and still is dominated by old and well-validated techniques such as PCR (polymerase chain reaction), or reverse transcriptase (RT)-PCR. However, CRISPR technology does have advantages over older techniques. For example, it is highly specific and can be carried out without the time-consuming thermal amplification steps and expensive machinery PCR requires.

Proof Diagnostics' CRISPR-based COVID-19 molecular test.
Proof Diagnostics’ CRISPR-based COVID-19 molecular test.

Due to the pandemic a lot of time and investment has been poured into developing new diagnostic technology, including tests powered by CRISPR. However, whether the COVID ‘silver lining’ will last remains to be seen.

“In a diagnostics company, you need to sell product and your value is a direct multiple of the revenue that you generate, whereas in a therapeutics company, you can sell hope for decades,” says Collins. “Without getting to a product, you can’t do that in a diagnostic space.”

While the increased accuracy offered by CRISPR diagnostics is, at least on paper, very attractive, the widespread use of lateralflow antigen tests during the pandemic has taught us that convenience and minimal cost can win over increased accuracy. Even competing in the more accurate ‘gold standard’ testing space occupied by PCR and RT-PCR tests could prove difficult, as these tests are so well established.

Eric Rhodes is the CEO of ERS Genomics, a company formed by Charpentier to license patents owned by the University of California, University of Vienna, and Emmanuelle Charpentier (CVC). “I think there will be applications where you want to use something like CRISPR, that it might have an advantage over the amplification required for PCR technology. But I don’t see it supplanting PCR technology and sequencing technologies, for
a variety of reasons,” says Rhodes.

Myhrvold is hopeful for the progress of CRISPR diagnostics, but acknowledges that a number of challenges need to be overcome before more widespread rollout can become a reality. “One of those is sample processing… it is challenging to make sure that you have something of good quality going into the test itself. A lot can go wrong at the very beginning, which then makes it impossible to get a good result no matter how good your technology is,” he explains.

“The other big one, I think, is manufacturing, which is a challenge for a lot of these new technologies. You need that mass production to drive down the cost. You can use something at a smaller scale, but it’s not really going to matter if the cost is now prohibitively expensive.”

It’s important to remember that it is early stages for CRISPR-based diagnostics, which have only been around for 5-6 years and are still in the early stages of development. “There is first generation CRISPR diagnostics, there’s been a second generation… and there’s this next generation of gene editing diagnostics that we’re trying to be a leader in,” says Shenai.

Dantas Lemburg is also hopeful for the future. “I really think it’s time for a change. I think the world today is more much more prone to accepting new technology. And I think CRISPR has demonstrated its capabilities, what it can do. I really believe we’re creating a next generation of molecular testing.”

The post The Evolution of CRISPR Technology from Editing to Diagnostics appeared first on Inside Precision Medicine.

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Breaking the tape

The top performers among drugs launched in 2020 were each the first of their kind.

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Breaking the tape

The top performers among drugs launched in 2020 were each the first of their kind.

By Joshua Slatko • josh.slatko@medadnews.com

The leaders in pharma’s Class of 2020 were all firsts. Veklury, for COVID, and Tepezza, for thyroid eye disease, were each the first drug of any kind to be approved by FDA for their respective disease targets. And while other treatments for migraine exist, Ubrelvy was the first orally administered calcitonin gene-related peptide (CGRP) receptor antagonist (gepant) for the treatment of migraine attacks once they start. The era of follow-ons in pharma may not entirely be over; but surely the industry’s researchers are still breaking barriers. 

Earning nearly $5.57 billion in sales during the product’s first full calendar year on the market, Veklury was the first drug approved by FDA for the treatment of COVID-19.

Veklury

The very first drug to be approved in the United States for the treatment of COVID-19, Gilead’s Veklury received emergency use authorization from FDA during May 2020, an expanded EUA three months later, and full approval for treating patients with COVID requiring hospitalization during October 2020. Veklury had originally been developed for the treatment of hepatitis C and had been studied in Ebola and Marburg virus, without success. 

FDA approval was based on three randomized controlled trials including final results of the National Institute of Allergy and Infectious Diseases’ double blind, placebo-controlled Phase III ACTT-1 trial, which showed that treatment with Veklury resulted in clinically meaningful improvements across multiple outcome assessments compared with placebo in hospitalized patients with COVID-19. Based on the strength of these data, Veklury became a standard of care for the treatment of COVID-19 in hospitalized patients.

In the randomized, double-blind, placebo-controlled ACTT-1 trial, Veklury significantly improved time to recovery as compared to placebo – by five days in the overall study population (10 versus 15 days) and seven days in patients who required oxygen support at baseline (11 versus 18 days). As a secondary endpoint, Veklury also reduced disease progression in patients needing oxygen, resulting in a significantly lower incidence of new mechanical ventilation or ECMO (13 percent versus 23 percent). In the overall patient population, there was a trend toward reduced mortality with Veklury compared with placebo at Day 29.

In June 2021, Gilead announced positive data from three retrospective studies of the real-world treatment of patients hospitalized with COVID-19, adding to the body of mortality and hospital discharge data for patients treated with Veklury. All three of the real-world analyses observed that, in the overall patient populations, patients who received Veklury treatment had significantly lower risk for mortality compared with matched controls. A reduction in mortality was observed across a spectrum of baseline oxygen requirements. The results were consistently observed at different time frames over the course of the pandemic and across geographies. Two of the studies also observed that patients who received Veklury had a significantly increased likelihood of discharge from the hospital by Day 28.

In January 2022, FDA granted expedited approval of a supplemental new drug application for Veklury for the treatment of non-hospitalized adult and adolescent patients who are at high risk of progression to severe COVID-19, including hospitalization or death. The expanded indication allowed for Veklury to be administered in qualified outpatient settings that can administer daily intravenous infusions over three consecutive days. FDA also expanded the pediatric EUA of Veklury to include non-hospitalized pediatric patients younger than 12 years of age who are at high risk of disease progression.

These actions by FDA came amidst a surge in COVID-19 cases and the reduced susceptibility to several anti-SARS-CoV-2 monoclonal antibodies (mAbs) due to the Omicron variant. In contrast, Veklury targets the highly conserved viral RNA polymerase, thereby retaining activity against existing SARS-CoV-2 variants of concern. In vitro laboratory testing has shown that Veklury retains activity against the Omicron variant. 

Quarterly sales, VekluryThe FDA sNDA approval, pediatric EUA expansion, and updated National Institutes of Health Treatment Guidelines for COVID-19 that additionally recommend Veklury for treatment in non-hospitalized settings were based on results from the PINETREE Phase III randomized, double-blind, placebo-controlled trial. The study evaluated the efficacy and safety of a three-day course of Veklury for intravenous use for the treatment of COVID-19 in non-hospitalized patients at high risk for disease progression. An analysis of 562 participants randomly assigned in a 1:1 ratio to receive Veklury or placebo, demonstrated that treatment with Veklury resulted in a statistically significant 87 percent reduction in risk for the composite primary endpoint of COVID-19 related hospitalization or all-cause death by Day 28 (0.7 percent, 2/279) compared with placebo (5.3 percent, 15/283). In the study, no deaths were observed in either arm by Day 28.

In February, Gilead released data demonstrating the in vitro activity of Veklury against 10 SARS-CoV-2 variants, including Omicron. Results of Gilead’s studies were consistent with other in vitro studies independently conducted by researchers from institutions in other countries, including Belgium, the Czech Republic, Germany, Poland and the United States, which confirmed Veklury’s antiviral activity against multiple previously identified variants of SARS-CoV-2, including Alpha, Beta, Gamma, Delta and Omicron.

The study analyzed in vitro antiviral activity by two methods to understand the susceptibility of 10 major SARS-CoV-2 variants to Veklury. The study results showed similar activity of Veklury against the variants and an early ancestral A lineage isolate detected in Seattle, Wash. (WA1 strain). Specifically, Delta and Omicron variants both remained fully susceptible to Veklury, and these laboratory results demonstrated that Veklury has remained active against all major variants isolated over the past two years.

In April, FDA approved a supplemental new drug application for Veklury for the treatment of pediatric patients who are older than 28 days, weighing at least 3 kg, and are either hospitalized with COVID-19 or have mild-to-moderate COVID-19 and are considered high risk for progression to severe COVID-19, including hospitalization or death. This approval made Veklury the first and only approved treatment for pediatric COVID patients in the United States. Under the expanded indication, a three-day Veklury treatment regimen is recommended to help prevent hospitalization in non-hospitalized COVID-19 pediatric patients who are at high risk for COVID-19 disease progression. For hospitalized pediatric patients who do not require invasive mechanical ventilation and/or ECMO, a five-day treatment course is recommended. The approval was supported by results from the CARAVAN Phase II/III single arm, open-label study, which demonstrated that Veklury was generally well-tolerated among pediatric patients hospitalized with COVID-19 with a high proportion of participants showing clinical improvement and recovery, as well as data from trials in adults.

Tepezza

Tepezza

Tepezza was the first drug ever approved by FDA for the treatment of thyroid eye disease.

When it earned approval in January 2020, Horizon Therapeutics’ Tepezza became the first and only FDA-approved medicine for thyroid eye disease, a serious, progressive and vision-threatening rare autoimmune disease that is associated with proptosis (eye bulging), diplopia (double vision), blurred vision, pain, inflammation, and facial disfigurement. Tepezza is a fully human monoclonal antibody (mAb) and a targeted inhibitor of the insulin-like growth factor-1 receptor (IGF-1R) that is administered to patients once every three weeks for a total of eight infusions.

The FDA approval of Tepezza was supported by a robust body of clinical evidence, including statistically significant, positive results from the Phase II clinical study, as well as the Phase III confirmatory clinical study OPTIC. The OPTIC study found that significantly more patients treated with Tepezza (82.9 percent) had a meaningful improvement in proptosis (≥ 2 mm) as compared with placebo patients (9.5 percent) without deterioration in the fellow eye at Week 24. Additional secondary endpoints were also met, including a change from baseline of at least one grade in diplopia (double vision) in 67.9 percent of patients receiving Tepezza compared to 28.6 percent of patients receiving placebo at Week 24. In a related analysis of the Phase II and Phase III clinical studies, there were more patients with complete resolution of diplopia among those treated with Tepezza (53 percent) compared with those treated with placebo (25 percent).

In October 2020, Horizon announced new long-term follow-up data from the Phase II clinical trial of Tepezza, which showed a sustained response up to one year following completion of treatment for thyroid eye disease. All patients with Week 72 data (37/37) reported some improvement in at least one of the study outcomes from baseline. 97 percent (36/37) of study participants had an improvement in clinical activity score (decrease of at least 1 point). 86 percent (31/36) had any decrease in proptosis. One patient chose elective TED surgery at Week 70 and did not have proptosis measurements at Week 72. Of patients with baseline diplopia, 70 percent (23/33) had an improvement of at least one grade. 70 percent (26/37) had disease inactivation (CAS of 0 or 1 point).

During December 2020, Horizon announced that the company expected a short-term disruption in Tepezza supply as a result of government-mandated COVID-19 vaccine production orders related to Operation Warp Speed that dramatically restricted capacity available for the production of Tepezza at its drug product contract manufacturer, Catalent. In March 2021, FDA cleared a prior approval supplement to the previously approved Biologics Licensing Application giving Horizon authorization to manufacture more Tepezza drug product resulting in an increased number of vials with each manufacturing slot. The company began to resupply the market in April, which ended the supply disruption.

Tepezza Quarterly SalesIn April 2021, new pooled data from the Tepezza Phase II and III trials was published in The Lancet Diabetes & Endocrinology. This data further reinforced that Tepezza significantly improves proptosis and diplopia for TED patients in different subgroups, with most maintaining a long-term response. There was no evidence for acute disease rebound (increase in percentage of patients no longer meeting proptosis, diplopia or ophthalmic composite outcome) seven weeks after the last dose of Tepezza. Proptosis (87 percent; 62/71), diplopia (66 percent; 38/58) and ophthalmic composite outcome (92 percent; 66/72) responses were observed seven weeks after the last dose of Tepezza. A post-hoc analysis of the composite ophthalmic outcome indicated that 81 percent (68/84) of Tepezza patients versus 44 percent (38/87) of placebo patients were responders at Week 24. Proptosis (67 percent; 38/57), diplopia (69 percent; 33/48) and composite outcome response (83 percent; 48/58) were observed 51 weeks after the last dose of Tepezza for those who had long-term off-treatment data available.

Additionally, in a post-hoc analysis, Tepezza-treated patients with more severe disease (those with ≥3 mm of proptosis and/or inconstant or constant diplopia) and those with less severe disease at baseline both experienced significant improvements in proptosis and diplopia. In patients with more severe disease, those treated with Tepezza had a proptosis response of 79 percent (50/63) compared to 17 percent (11/65) of those who received placebo, and a diplopia response of 68 percent (38/56) compared to 31 percent of those who received placebo (15/49). In patients with less severe disease, those treated with Tepezza had a proptosis response of 71 percent (15/21) compared to 9 percent in those who received placebo (2/22), and a diplopia response of 80 percent (8/10) compared to 30 percent in placebo (3/10).

In post-hoc analyses, patients who received Tepezza in both the lower baseline CAS subgroup (4 or 5) and the higher CAS subgroup (6 or 7) demonstrated statistically significant improvements compared with placebo in proptosis and diplopia. Overall response and CAS of 0 or 1 response also improved.

Post-hoc analysis from the Phase III study also demonstrated that in patients treated with Tepezza, those with higher (≥10 IU/L) or lower (<10 IU/L) serum thyrotropin-binding inhibitory immunoglobulin (TBII) baseline levels both had a proptosis response (mean reduction of -3.65 mm and -3.01 mm, respectively) with no treatment difference between the two groups. In patients with higher baseline TBII, 71 percent (10/14) of patients who received Tepezza experienced an improvement in diplopia compared to 23 percent (3/13) of patients who received placebo.

In November 2021, Horizon announced findings of a real-world adherence analysis of Tepezza for the treatment of TED. The analysis found that more than 90 percent (n=995) of people who were prescribed Tepezza for TED went on to complete all eight infusions, indicating a high level of adherence to the medicine in clinical practice. The study evaluated 1,101 people living with TED (71 percent female, mean age 58 years) who started treatment with Tepezza prior to July 2020. Non-compliance was low at approximately 1 percent (n=15). Only 8 percent (n=84) reported that they discontinued because of adverse events.

In June 2022, Horizon announced results of a new analysis examining rates of hyperglycemia among patients treated with Tepezza for TED compared to placebo in the Phase II and OPTIC Phase III clinical trials. The analysis found a total of nine adverse event reports of hyperglycemia in eight patients (8/84, 10 percent) who received Tepezza, and one patient (1/86; 1.2 percent) who received placebo. The majority (5/8, 63 percent) of patients who experienced hyperglycemia while taking Tepezza had pre-existing diabetes. Of the hyperglycemic AEs reported in the Tepezza-treated patients, all were controlled with medicine. All reported AEs were grade 1 (>ULN-160mg/dl) or grade 2 (161 – 250mg/dl), and none led to study discontinuation. HbA1c levels increased by 0.22 percent in those treated with Tepezza compared to 0.04 percent among placebo patients.

Ubrelvy

Ubrelvy

Ubrelvy was the first orally administered calcitonin gene-related peptide receptor antagonist (gepant) to be approved by FDA for the treatment of migraine attacks once they start.

Approved by FDA in late December of 2019, Ubrelvy was the first orally administered calcitonin gene-related peptide (CGRP) receptor antagonist (gepant) for the treatment of migraine attacks once they start. Ubrelvy works by blocking CGRP, a protein that is released during a migraine attack, from binding to its receptors. It works without constricting blood vessels, which some older treatments were known to do. FDA’s approval was based on four clinical studies (ACHIEVE I, ACHIEVE II, UBR-MD-04, and 3110-105-002), which demonstrated efficacy, safety, and tolerability of orally administered Ubrelvy in the acute treatment of migraine. Both 50 mg and100 mg dose strengths demonstrated significantly greater rates of pain freedom and freedom from the most bothersome migraine-associated symptom at two hours, compared with placebo. Ubrelvy joined AbbVie’s portfolio when that company completed its acquisition of Allergan in May 2020. 

In August 2020, AbbVie announced Serena Williams as the spokesperson for Ubrelvy to raise awareness of an effective acute treatment option for people living with migraine. The multichannel marketing campaign featuring Williams highlighted how Ubrelvy works for people with different lifestyles by helping individuals treat their migraine attacks anytime, anywhere. As spokesperson, she was featured in a video, available on social media, talking with neurologist and paid AbbVie consultant Dr. Jennifer McVige about her experience with migraine and Ubrelvy. Williams was also included in print and digital advertising and other marketing initiatives.

In September 2021, FDA approved Abb­Vie’s Qulipta, another drug from the gepant family, for the preventive treatment of episodic migraine in adults. Qulipta is the first and only oral calcitonin gene-related peptide receptor antagonist specifically developed for the preventive treatment of migraine. The approval was supported by data from a robust clinical program evaluating the efficacy, safety, and tolerability of Qulipta in nearly 2,000 patients who experienced 4 to 14 migraine days per month, including the pivotal Phase III ADVANCE study, the pivotal Phase IIb/III trial, and the Phase III long-term safety study.

Ubrevly quarterly salesIn the pivotal Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group ADVANCE trial, the primary endpoint was change from baseline in mean monthly migraine days across the 12-week treatment period. All Qulipta dose groups met the primary endpoint and demonstrated statistically significant reductions in mean monthly migraine days compared to placebo. Patients treated with 60 mg of Qulipta across 12 weeks experienced a 4.2-day reduction from baseline of 7.8. A key secondary endpoint in the ADVANCE trial measured the proportion of patients that achieved a ≥50 percent reduction in monthly migraine days across the 12-week treatment period. The trial demonstrated that 56 percent/59 percent/61 percent of patients in the 10 mg/30 mg/60 mg Qulipta arms, respectively, achieved a 50-100 percent reduction, compared to 29 percent of patients in the placebo arm.

During June, AbbVie submitted a supplemental NDA to FDA for Qulipta to support the preventive treatment of chronic migraine in adults. If approved, Qulipta would be the first gepant cleared for the broad indication of the preventive treatment of migraine, including episodic and chronic. The supplemental NDA submission includes data from the pivotal Phase III PROGRESS trial in patients with chronic migraine, which supplements the existing data in episodic migraine. People living with chronic migraine experience headaches for 15 or more days per month, which, on at least eight of those days per month, have the features of migraine.

The Phase III PROGRESS trial met its primary endpoint of statistically significant reduction from baseline in mean monthly migraine days compared to placebo across the 12-week treatment period in adults with chronic migraine. The trial also demonstrated that treatment with Qulipta 60 mg once daily (QD) and 30 mg daily (BID) resulted in statistically significant improvements in all six secondary endpoints. This includes a key secondary endpoint that measured the proportion of patients that achieved at least a 50 percent reduction in mean monthly migraine days across the 12-week treatment period. 

Josh Slatko, Med Ad News Josh Slatko is contributing editor of Med Ad News and PharmaLive.com.

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The biopharma industry’s response to the global pandemic has propelled some COVID-19 vaccines into the leading ranks of the world’s best-selling products,…

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Over the top

The biopharma industry’s response to the global pandemic has propelled some COVID-19 vaccines into the leading ranks of the world’s best-selling products, with Pfizer/BioNTech’s Comirnaty surpassing AbbVie’s Humira for the No. 1 spot.

By Andrew Humphreys • andrew.humphreys@medadnews.com

The ripple effects of the worldwide COVID-19 pandemic continue to be felt throughout the biopharmaceutical realm, from allocation of business resources to the revenue impact of new vaccines and treatments for the industry’s main players. No biopharma company has thrived more during the pandemic’s reign than Pfizer, which experienced the largest increase in market capitalization during 2021 at $127 billion, rising to $331 billion. 

Comirnaty became the first COVID-19 vaccine to gain full approval.

Pfizer has collaborated with BioNTech to jointly develop the mRNA-based coronavirus vaccine Comirnaty/BNT162b2 to help prevent COVID-19. Comirnaty/BNT162b2 accounted for 45 percent of Pfizer’s total revenue during 2021, coming in at $36.78 billion. For the first six months of 2022, Pfizer reported Comirnaty direct sales and alliance revenue of $22.08 billion. As of July 28, Pfizer forecasted $32 billion in revenue for Comirnaty for full-year 2022, with gross profit to be split evenly with BioNTech, which includes doses expected to be delivered throughout the fiscal year. 

Comirnaty is based on Bi­oN­Tech’s proprietary messenger RNA technology. As the first-ever approved mRNA therapy, Comirnaty additionally represents BioNTech’s first commercial product. Through the vaccine, BioNTech’s revenue grew from €482.3 million ($571 million) in 2020 to €18.98 billion ($22.45 billion) for 2021. In reporting first-quarter 2022 results, BioNTech reiterated the company’s prior full-year 2022 financial year outlook of €13 billion ($15.4 billion) to €17 billion ($20.11 billion).

Pfizer-BioNTech’s COVID-19 vaccine is authorized by the U.S. Food and Drug Administration under Emergency Use Authorization (EUA) for active immunization to prevent coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 6 months of age and older. Comirnaty (approved under a Biologics License Application)/BNT162b2 (authorized under EUA) in July 2022 became the first COVID-19 vaccine to be granted FDA approval for adolescents 12 years and older, following U.S. emergency use authorization in May 2021. Comirnaty became the first FDA-approved COVID-19 vaccine for individuals 16 years and older during August 2021. 

The impact of the worldwide pandemic led to the unseating of Humira (adalimumab) as the world’s top-selling pharmaceutical product in 2021, which was the medicine’s best-performing year ever. Humira has annually been the best seller among prescription medicines dating back to 2012. The drug’s combined revenue for 2021 between AbbVie and Japan’s Eisai topped $21.18 billion. AbbVie reported $20.69 billion of that total, the first time Humira broke the $20 billion barrier in one year for the North Chicago-based company. For first-half 2022, AbbVie reported Humira worldwide revenue of $10.1 billion.Humira

Humira is administered as a subcutaneous injection. The biologic therapy is approved for treating various autoimmune diseases in North America and in the European Union: rheumatoid arthritis (moderate to severe), psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease (moderate to severe), plaque psoriasis (moderate to severe chronic), juvenile idiopathic arthritis (moderate to severe polyarticular), ulcerative colitis (moderate to severe), axial spondyloarthropathy, pediatric Crohn’s disease (moderate to severe), hidradenitis suppurativa (moderate to severe), pediatric enthesitis-related arthritis, non-infectious intermediate, posterior and panuveitis, pediatric ulcerative colitis (moderate to severe), and pediatric uveitis. Humira is approved in Japan for treating intestinal Behçet’s disease and pyoderma gangrenosum.

Humira is sold in other markets around the globe, including Japan, China, Brazil, and Australia. The medication accounted for 37 percent of AbbVie’s total net revenue during 2021 and nearly 36 percent during the first six months of 2022.

Moderna’s COVID-19 vaccine Spikevax (mRNA-1273) has been authorized for use or approved in more than 70 countries. The FDA fully approved the BLA for Spikevax for individuals 18 years of age and older in January 2022. Moderna’s COVID-19 vaccine was made available under EUA in the United States on Dec. 18, 2020. The full licensure of Spikevax in the United States joined that in Canada, Japan, the European Union, the UK, Israel, and other countries where the adolescent indication is additionally approved. 

During June 2022, Moderna gained EUA from the FDA for the company’s COVID-19 vaccine mRNA-1273 in young children ages 6 months through 5 years of age at a dose level of 25 µg. Moderna has additionally received emergency use authorization for a 50 µg two-dose regimen of mRNA-1273 for children ages 6 through 11 years old and a 100 µg two-dose regimen for adolescents aged 12 through 17 years old. 

Spikevax marks Moderna’s first commercial product. Sales amounted to nearly $17.68 billion during full-year 2021. For the first six months of 2022, Moderna reported product sales of about $10.46 billion.

Keytruda ranks as the world’s top-selling cancer therapeutic. Global sales for Merck’s checkpoint inhibitor grew from $11.08 billion during 2019 to $14.38 billion for 2020 and $17.19 billion in 2021. For first-half 2022, Merck reported Keytruda global sales of $10.06 billion. The anti-PD-1 (programmed death receptor-1) therapy contains the active chemical pembrolizumab.

Keytruda

Keytruda works by increasing the ability of the body’s immune system to help detect and fight tumor cells. The humanized monoclonal antibody blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes that may affect both tumor cells and healthy cells.

Outside the COVID-19 vaccine domain, Keytruda is expected to overtake Humira as the top-selling prescription medicine in 2023 when the latter’s U.S. market exclusivity is set to expire. AbbVie has entered into settlement and license deals with several adalimumab biosimilar manufacturers. The licenses in the United States will start during 2023 and the licenses in Europe began in 2018. “The inevitable arrival of Humira biosimilars in the U.S. next year means that AbbVie is hurtling towards biopharma’s biggest-ever patent cliff,” according to Evaluate Pharma analysis.

Meanwhile, Keytruda is anticipated to continue thriving as the product’s compound patent is protected from expiration in all majors markets until at least 2028 (the United States and China) and into the following decade in the EU and Japan. 

According to analysts from Evaluate Pharma, come 2028, Keytruda will remain the top-selling non-Covid treatment with estimated sales of $30.9 billion. By that year, the top-selling pharmaceutical of all-time, Humira, will no longer be a member of the top 10 sellers (see graphic on this page). 

Per Evaluate Pharma, the No. 2 seller in 2028 is projected to be Bristol Myers Squibb and Ono Pharmaceutical’s Opdivo (nivolumab), predicted to trail Keytruda by nearly half in revenue at $15.7 billion. A fully human monoclonal antibody that binds to the PD-1 on T and NKT cells, the biological product Opdivo has received approvals for various anti-cancer indications including bladder, blood, colon, head and neck, kidney, liver, lung, melanoma, mesothelioma and stomach.

Biggest Selling Drugs, Evaluate Pharma

Download the listing of the top 200 medicines based on global sales during 2021

Andrew Humphreys is contributing editor of Med Ad News and PharmaLive.com.

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Economics

Braxia and KetaMD, CEOs McIntyre and Gumpel Speak on Acquisition

Last week, the Canadian company Braxia Scientific acquired 100% of the issued and outstanding stock of KetaMD, Inc. This is an exciting acquisition, and…

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Last week, the Canadian company Braxia Scientific acquired 100% of the issued and outstanding stock of KetaMD, Inc. This is an exciting acquisition, and in today’s interview, The Dales Report’s Nicole Hodges talks with CEOs Dr. Roger McIntyre and Warren Gumpel of Braxia Scientific and KetaMD respectively.

For some background information, KetaMD is a U.S. based, privately-held, innovative telemedicine company, with a mission to address mental health challenges via access to technology-facilitated ketamine-based treatments. Braxia Scientific is Canada’s first clinic specializing in ketamine treatments for mood disorders. They recorded revenue of $1.49m for 2022 fiscal year, ended March 31. On a year-over-year basis, revenue increased 47.5%.

Here’s some highlights from the interview.

KetaMD gives Braxia a presence in the US

Dr. McIntyre says that KetaMD gives Braxia what they’ve had as their vision from the beginning: a US presence. KetaMD is a living program. It’s already running, has infrastructure, and patients. McIntyre believes that a program like KetaMD is something Braxia’s needed to scale and obtain commercial success.

With telemedicine, Braxia has a potential to serve a gap in access. The zeitgeist of “patient going to medicine” has flipped, McIntyre says. “Now it’s medicine goes to the patient, and that is long overdue.”

COVID speeding a trend that was already happening

In 2020, 80% of physicians indicated they had virtual visits. That’s a number up from 22% the year before. But this is something that many doctors, McIntyre included, believe always should have happened. The pandemic only was the catalyst for innovation and making the option viable.

While some treatments will always need a clinic or a hospital, McIntyre believes some treatments can be done safely at home. And they are, for many chronic diseases. He feels implementing ketamine and psychedelics would be among these treatments where service could be expanded into the home. It would require careful SOPs in place, best practices, and surveillance. But he believes Braxia Scientific could deliver this with KetaMD.

Gumpel to stay as CEO of KetaMD

Gumpel says that KetaMD benefits in this acquisition from being part of the world’s most prominent researchers in depression, psychedelics, and ketamine. In the acquisition, he’ll stay on as CEO. He admits that Dr. McIntyre has been a huge part of collecting the data on the safety of ketamine treatment, and has a strong motivation to “see this thing through until most of society can access that – or at least the people that need it and want it.”

Gumpel admits he has a personal connection to ketamine treatment. As a person who has experienced bouts of depression for years, it saved his life, he says. He is grateful he was living within walking distance of ketamine treatment in Manhattan. It made him extremely aware of the accessibility gap, which in part inspired KetaMD.

Be sure to tune in for the full interview regarding Braxia and KetaMD, right here on The Dales Report!

The post Braxia and KetaMD, CEOs McIntyre and Gumpel Speak on Acquisition appeared first on The Dales Report.

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