Invitae has reportedly denied that it is in discussions to be bought by Exact Sciences after rumours of this deal surfaced last week. But it might want to reconsider, or at least contemplate other deal making, given that the flagship liquid biopsy for which it bought Archer DX last year will not get approved in the hoped-for timeframe. Stratafide, a tumour-agnostic test designed to guide therapy for cancer patients, must achieve US approval by March 31, 2022 to trigger a $262.5m milestone payment to Archer DX’s shareholders. Based on FDA feedback, Invitae no longer considers this possible, it disclosed in an SEC filing, and it has written off the liability connected to the milestone. It is not clear if new trials might be needed, or exactly when Stratafide’s approval or clearance might arrive. But, if it is approved, the test will enter a market already occupied by Guardant Health and Roche – and every month it is delayed allows these much larger groups to solidify their leads. Being merged into Exact would certainty give Invitae more firepower. Given that Invitae currently has around $1.1bn in cash, however, it is perhaps more likely to conduct M&A of its own.
Wednesday, August 11, 2021
Will Astra walk away from roxadustat?
After last month's damning adcom for Fibrogen’s roxadustat today’s complete response letter raises the very real possibility that the group's partner Astrazeneca will choose not to hang around for much longer. For now Astra is keeping the faith, and roxa does have other clinical catalysts on the horizon that Astra might want to see before making a decision. The Whitney phase 2 chemotherapy-induced anaemia trial is due to read out this quarter, but readout of the phase 3 Matterhorn study, in myelodysplastic syndromes, has been delayed from the first half of 2022 to as late as the first half of 2023. Even if Astra does hang around it is unlikely to commit more money to roxa’s US future, which as of today hinges on a whole new clinical study. Fibrogen might have little choice but to trigger a major restructuring to pivot to its next best option, the IPF project pamrevlumab. Roxa still has a chance in Europe, where it received a positive CHMP decision in June. But even if the EMA follows through with approval this will be little consolation to Fibrogen, whose stock has slid 77% in the past six months.
I-Mab thinks cytokine storm drug can rival Humanigen lenzilumab in sickest COVID patients
I-Mab’s experimental COVID-19 treatment reduced the mechanical ventilation rate in patients, putting the Chinese biotech in the game with Humanigen in trying to improve treatment options for the sickest patients.
The ongoing phase 2/3 study is testing I-Mab’s plonmarlimab for the treatment of cytokine release syndrome, an over-active immune response associated with a higher death rate in COVID-19 patients.
Currently, physicians treat such severe patients with steroids and Gilead’s remdesivir, but there remains a need for more efficacious therapies, especially as the new Delta variant grips the U.S. and the world, bumping up hospitalizations once again.
I-Mab’s therapy targets a certain cytokine that plays a critical role in acute and chronic inflammation. The study’s main goal is to examine plonmarlimab’s safety, efficacy and effect on cytokine levels in patients with severe COVID-19.
Plonmarlimab, or TJM2, improved the rate of mechanical ventilation free treatment compared to placebo, at a rate of 83.6% vs 76.7% by day 30. The therapy was also associated with a lower mortality rate of 4.9% vs 13.3% and higher recovery rates. I-Mab also said the therapy reduced recovery time and hospitalization duration.
There’s a lot to unpack there, and the details were short in I-Mab’s statement. Many of the improvement percentages compared to placebo are not too far off—but they could be significant to these very sick patients who have few other options.
I-Mab threw down the gauntlet against Humanigen, which has a COVID-19 therapeutic already under review in the U.S. and U.K. Lenzilumab also tries to stop cytokine storms.
“The magnitudes of the clinical improvements are comparable to those observed with lenzilumab in a similar patient population,” I-Mab said.
Humanigen has estimated that lenzilumab caused 37% more recoveries than standard of care in hospitalized COVID-19 patients in a phase 3 trial.
The study has an adaptive trial design, meaning patients can only stay enrolled if the interim analysis shows an average improvement in recoveries of 29% or more. The improvement rate was calculated based on enrollment requested by the data safety monitoring board.
Whether the two therapies can be compared apples to apples remains to be seen, as they are not examining the exact same outcome. But improvement is improvement when a patient has severe COVID-19, and drug regulators are scrambling to incentivize the development of more effective treatments.
Analysts have predicted that Humanigan's drug could become the standard of care for the sickest hospitalized COVID-19 patients and bring in $1 billion in sales in the first 12 months after approval. GlaxoSmithKline is also investigating a cytokine release drug.
Novartis, Pfizer, Gilead roll out COVID vax rules as delta makes case for mandates
Right as several countries seemed to be getting a handle on the COVID-19 pandemic, the delta variant crashed onto the scene, sending case counts soaring again and throwing re-opening plans into limbo. With cases expected to continue ticking up before Labor Day, the argument for vaccine mandates is growing.
For many drugmakers, several of whom led the charge on the therapeutics and vaccines taking aim at the pandemic, vaccination requirements are becoming the norm. Meanwhile, a number of biotechs have been able to forego mandates altogether because their smaller size means their workforces are already fully vaccinated.
Over the past few days, Fierce Pharma asked a range of biopharmas big and small about their evolving vaccination policies. While some companies have already gone public with their plans, others are deliberating how to approach the issue. Here's how several companies are handling it.
Novartis has set the expectation among its workers that “everyone” coming to its campuses either needs to be vaccinated or have a negative COVID-19 test result within the last 14 days before each site visit, a company spokesperson said over email. Concerned about delta and other potential virus variants lurking around the corner, Novartis is “strongly” encouraging all of its staffers to get vaccinated as soon as possible. The company will keep tabs on the situation and update its policy as the pandemic continues to evolve, the spokesperson added.
Gilead Sciences will also require all U.S. employees and contractors to be fully vaccinated. Its policy will take effect on October 1, the company said Monday, adding that the mandate will only be in place where legal and where vaccines are “readily available.” The company forged its policy after tracking the rise of COVID-19 cases in the U.S. and abroad, as well as analyzing the data available on COVID-19 vaccines’ power to curb infections, hospitalizations and deaths.
Gilead says it polled its employees “extensively” on the issue. It plans to accommodate staffers who can’t get a vaccine on medical or religious grounds. In places where vaccine mandates aren’t legal, the antiviral specialist says it will “strongly recommend” employees get the shot.
In a bid to “best protect the health and safety of our colleagues and the communities we serve,” Pfizer is also requiring all U.S. staffers and contractors get vaccinated or undergo regular weekly testing, the company told CNBC last week.
The company is “strongly encouraging” vaccinations for all ex-U.S. employees who can get one, spokesperson Pamela Eisele told the news outlet. Like Gilead, the company says it will work with employees toward an alternative solution if they have medical or religious objections to the shot.
Roche's Genentech has also jumped on the mandate bandwagon, San Francisco Business Times reports. The company has said about 80% of its staffers nationwide have self-reported as fully vaccinated.
"However, with the rise of the delta variant, we believe we must do even more to guard against the spread of the virus at our sites and the serious risk this would pose to our people and operations," Genentech told the publication.
On the biotech front, many smaller companies are adopting a gentler tack. All of CAMP4 Therapeutics’ workers have been vaccinated, which CEO Josh Mandel-Brehm flagged in an email as one of the “benefits” of being a small company. The programmable therapeutics outfit isn’t requiring vaccines, but it does have a mask mandate for those who haven’t received the shot, Mandel-Brehm said.
It’s a similar story over at IM Therapeutics. The company hasn’t implemented a vaccine mandate and has “not needed to,” because all its current employees voluntarily received the shot, a spokesperson said over email.
Double Rainbow Biosciences and Cellino reported similar moves, telling Fierce Biotech they hadn’t introduced an official vaccine policy. In Double Rainbow’s case, “100%” of the company’s employees are fully vaccinated, Grant Smith, Double Rainbow’s director of corporate communications, said. The company has also reintroduced a mask requirement for its in-office staff after the CDC released its updated delta guidance in late July. Meanwhile, all Cellino staffers coming into the office have been vaccinated, CEO Nabiha Saklayen said in an email.
Other companies have bypassed shot mandates altogether or adopted more of a “wait and see” approach.
For its part, Alnylam told Fierce Pharma it hasn’t introduced a vaccine mandate yet, but it’s “moving in that direction.” The company believes “the science supports this and it’s the right thing to do for society,” a spokesperson said in an email.
Immuno-oncology specialist Agenus said in an email that it doesn’t have a vaccine mandate for its employees. Biogen, meanwhile, declined to comment on its policy.
GlaxoSmithKline lands somewhere in the middle. GSK currently requires that employees show proof of vaccination to enter "a number of [its] U.S. sites," a spokesperson said over email. It's entertaining some exemptions, the spokesperson added. GSK isn't demanding workers get the vaccine but "strongly" encourages it for employees and "complementary workers for whom it is appropriate."
Bayer isn't requiring the vaccine for its U.S. employees either, though it will continue to track the situation and adjust its policies accordingly, the company said over email.
Boehringer Ingelheim isn’t mandating vaccines in Germany or the U.S., though it’s urging its workers get the shot on both sides of the Atlantic, the company said in an emailed statement. In Germany, where roughly 30% of the company’s workforce is based, Boehringer Ingelheim has administered some 9,000 vaccinations to its employees and their families on its sites.
Vaccines are voluntary for the company’s U.S. staffers, too, though Boehringer Ingelheim stated unequivocally that it believes the shots are “the most effective tool in the fight against the COVID-19 pandemic.” Stateside, the company has provided its employees and their families with free vaccination clinics across a number of its U.S. locations.
With delta "dominating" and Lambda "lurking," RBC Capital Markets analysts wrote to clients Tuesday that they expect daily COVID-19 cases to rise steadily until the start of a "[meaningful]" decline right before Labor Day. They forecasted a peak of 250,000 to 300,000 daily cases in the U.S. some 25 to 27 days from now.
The analyst team foresees another 115,000 COVID-related deaths in the U.S. between now and the end of the year, crediting "higher than expected" case counts and stressed hospital bandwidth.
Merck, Novo, Sanofi win China growth thanks to pricing; anxiety on biologics outlook
In China, Big Pharma companies know all too well that their off-patent drugs face intense pressure from a relatively new price-cutting scheme. In response, many are turning to newer offerings for growth while trying to stabilize their established medicines departments. Overall, the strategy is working.
AstraZeneca, Bayer, Eli Lilly, Merck & Co., Novartis, Novo Nordisk and Sanofi are among Western drugmakers that reported pharma sales growth from China during the first half of 2021.
But even as innovative products such as AZ’s lung cancer med Tagrisso, Merck’s HPV vaccine Gardasil and Novartis’ immunology drug Cosentyx ginned up sales increases, pharma companies have also found themselves playing defense for their mature brands. Plus, that continually expanding price-cutting program now looks ready to tap into biologics, starting with insulins.
Over the last few years, AstraZeneca has established itself as the leading foreign drugmaker in China. The company's sales in the country jumped 11% at constant currencies to $3.21 billion in the first half of the year.
Despite having to offer big discounts, AZ has worked hard to get its drugs onto China’s National Reimbursement Drug List (NRDL). Tagrisso’s use in newly diagnosed EGFR-mutated non-small cell lung cancer and Lynparza’s indication for first-line maintenance treatment of BRCA-mutated ovarian cancer after one round of chemotherapy recently scored inclusion on the list starting back in March.
What’s more, AZ is “maximizing” Farxiga, known as Forxiga outside the U.S., AZ’s China and international market head Leon Wang said during a conference call a few days ago. The SGLT2 drug in October had its cardiovascular outcomes benefit added to its China label and scored approval in February to reduce heart-related death and hospitalization in patients with heart failure with reduced ejection fraction.
For Merck, which is AZ’s collaborator on Lynparza, China sales grew 33.7% year-over-year to $1.70 billion in the first half. The growth was “really driven by Gardasil,” Merck’s president of human health, Frank Clyburn, said during the company’s recent quarterly conference call.
Since China’s approval for Gardasil 9 in 2018, demand for the HPV vaccine has continuously outstripped supply. Looking forward, Merck expects strong China sales for the vaccine because it has so far only reached a small number of eligible recipients, Clyburn said.
Besides Gardasil, Merck’s alliance revenue for Eisai-partnered liver cancer med Lenvima increased by 15% at constant currencies in the second quarter to $181 million. The growth came thanks to the drug’s recent inclusion on China’s NRDL, Clyburn said.
But generic pressures could soon come for the cancer med.
After defeating Eisai’s key patents, two generic versions by Simcere Pharma and Chia Tai Tianqing Pharma have just won local go-aheads a few days ago.Another company benefiting from a recent NRDL inclusion is Novartis. Cosentyx, currently the Swiss pharma’s top-selling med, quadrupled China sales in the second quarter compared with the first quarter following the listing in March, Novartis’ pharma chief Marie-France Tschudin told investors on a call a few days ago. In addition to Cosentyx, Novartis also scored new NRDL spots for blood disorder drug Promacta and BRAF-MEK cancer duo Tafinlar and Mekinist.
Meanwhile, Novartis' popular heart med Entresto tripled sales year over year in China, making the country its second-biggest market behind the U.S. In June, Entresto won a China nod for treating essential hypertension, an indication that’s not yet included on the drug’s U.S. label.
Overall, Novartis’ China business posted sales gains of 18% at constant currencies to $811 million in the second quarter. As CEO Vas Narasimhan noted during the conference call, the company is “on track on our stated goal to double the size of our China business from the 2020 baseline” by around 2024 to 2025.
For its part, Lilly enjoyed 35% growth in China during the second quarter “as sales of new medicines have accelerated significantly in the past three quarters,” company chief financial officer Anat Ashkenazi said during a call last week. These include Innovent Biologics-partnered PD-1 inhibitor Tyvyt. As the first PD-1 to snag an NRDL status a year ago, the drug’s revenue in China nearly doubled during the first six months of the year to $214.6 million.
In addition to those companies, Bayer’s pharma unit recorded 22% growth in China during the second quarter thanks to heart drug Xarelto. Sanofi’s China business grew sales by 6.3% at unchanged exchange rates during the first half to €1.38 billion ($1.62 billion). Novo Nordisk saw China sales increase reach DKK 8.05 billion ($1.27 billion) after a 12% year-over-year increase at constant currencies.
Aiming to lower drug costs, China in 2018 rolled out a new program designed to bring down the prices of off-patent drugs. This so-called volume-based procurement (VBP) program pits generic makers against the originators to win large tenders from public hospitals.
Some companies have chosen to distance themselves from off-patent products—a strategy that doesn’t necessarily focus solely on China.
In this group, Pfizer has offloaded its Upjohn established medicines to Mylan to form Viatris. Merck has spun off its aging meds—along with the women’s health and biosimilars portfolio—into Organon. Takeda recently sold off some cardiovascular and metabolic drugs in the Chinese mainland to local firm Hasten Biopharmaceutic. Lilly a few days ago just divested Chinese rights to erectile dysfunction therapy Cialis to Menarini.
Merck’s China performance lately “ties very well through our strategy where we pivoted and focused more on our innovative portfolio,” Clyburn said on the company’s conference call. That’s why the company is “very confident in the future growth within China,” he added.
But many foreign pharmas still maintain a sizeable business for off-patent drugs. Those companies have typically suffered losses from the VBP program.
AstraZeneca, for its part, cited the program’s effect on blood thinner Brilinta as the main reason for its emerging markets pullback so far this year. Tagrisso predecessor Iressa, cholesterol med Crestor and proton pump inhibitor Nexium are all still reeling from the effect of the VBP program. And asthma inhalation Pulmicort will start facing the assault in October.
Still, not all older drugs have suffered from VBP. For example, Sanofi’s blood clot buster Plavix managed an 8% sales growth in China to €94 million in the second quarter. The performance came more than a year after its inclusion in the VBP.
The more dreadful outcomes lie in what’s yet to come. In July, China’s National Healthcare Security Administration gathered insulin developers to discuss potential VBP rounds of the key diabetes drug class. Many industry watchers feared that the move could tee up potential inclusion of biologic drugs and their biosimilars in the future. The VBP program has so far only focused on small molecules.
After talking to authorities at the July meeting, Novo believes “it's less likely” that insulins will be included for VBP this year, company CEO Lars Fruergaard Jørgensen said during its second-quarter call on Friday. But an insulin VBP “will eventually happen,” he added.
“If you want to do a VBP for a biologic, and not least life-saving medicine like an insulin, this is not a trivial thing to do to secure both volumes and quality of those volumes,” Jørgensen said.
Despite the recent introduction of GLP-1s such as Ozempic in China, insulin products still make up the majority of Novo’s sales in the country. In the first half of the year, Novo’s insulin sales reached DKK 6.20 billion (nearly $1 billion) in China, up 10% at constant currencies over the same period last year. By comparison, the Danish pharma’s GLP-1 sales in the country were DKK 833 million ($131 million) during the period after a 68% year-over-year growth.
Novo is currently the top insulin maker in China with a 50.8% market share as of May, the company said.
Another major insulin player, Sanofi, remains “vigilant to learn about any potential mechanism for the inclusion of the insulin class,” Sanofi’s general medicines head, Olivier Charmeil, told investors on the company's second-quarter call.
“The exact mechanism, the scope, the timing is not known, and we feel very confident, given our track record in managing VBP in our ability now to grow volume,” he added.
Restructuring at FibroGen could be next step
After an overwhelmingly negative opinion from an external FDA advisory panel, AstraZeneca and FibroGen’s potential first-in-class anemia drug roxadustat looked unlikely to pass muster with the U.S. regulators. Now, the second shoe has dropped. As one analyst sees it, a restructuring at FibroGen could be next.
The FDA has issued a complete response letter for roxadustat’s application in anemia associated with chronic kidney disease, FibroGen said Wednesday. The rejection covers both patients who require dialysis and less sick, nondialysis-dependent individuals.
The FDA has requested additional clinical studies if FibroGen wants to shoot for an approval ever again. But as SVB Leerink analyst Geoffrey Porges observed in a note last month after the advisory committee vote, AZ’s and FibroGen’s investors likely won’t be willing to fund an additional phase 3 trial for the ill-fated med. Without revenue contributions from roxa in the U.S., FibroGen will need an overhaul to keep the business afloat, Porges has said.
It’s not immediately clear whether FibroGen and its partner AZ plan to run additional trials to support a potential U.S. refiling. In their statements Wednesday, both companies said they’re working to evaluate the next steps.
The FDA's complete response letter wraps up a roller-coaster clinical and regulatory path for roxa in the U.S. As the first member of the HIF-PHI drug class to win an approval anywhere in the world, roxa once bore blockbuster expectations based on the notion that it was at least as effective as and safer than Amgen and Johnson & Johnson’s standard-of-care erythropoietin therapies Epogen and Procrit.
But safety concerns came to the fore in April, when FibroGen revealed that its data on the med incorporated different analytical criteria than were specified before the trial. An analysis based on the prespecified criteria
practically erased roxa’s presumed safety advantage.Then, an FDA internal review document outlined a slew of new safety problems previously unknown to investors. After digging into clinical trial data, the FDA reviewers linked roxa to increased risk of death, blood clots, serious infections and more compared with erythropoietin therapy in the dialysis-dependent population and with placebo in the nondialysis-dependent group.
Concurring with the FDA staffers’ concerns, panelists at an advisory committee voted 13-1 against roxa’s approval in non-dialysis patients and 12-2 against for dialysis-dependent patients during a July meeting.
Once the votes came through, SVB Leerink’s Porges immediately suggested that FibroGen investors should demand a restructuring. The company “should become at least one-third smaller,” he wrote in a note to clients on July 16. The analyst went as far as flagging the “perils of trusting FibroGen’s data, management and board.”
During a Monday conference call centered on FibroGen’s second-quarter performance, CEO Enrique Conterno said that those “directly responsible” for the safety data error were no longer with the company.
“Management is taking steps to ensure the company's processes are consistent with best practices in all respects,” Conterno said. The company plans to install independent quality oversight of clinical data management, programming, analysis and reporting, the CEO added.
As an FDA rejection looked almost inevitable by the time of the conference call, FibroGen’s focus had clearly shifted to ex-U.S. opportunities.
In China, roxa sales reached $96.3 million in the first half of 2021 and the business has become profitable, Conterno said. FibroGen’s commercial partner AZ—a powerful marketing presence in China—is expanding the drug’s reach, he said. By the end of June, roxa was listed at hospitals that cover about 81% of the entire chronic kidney disease anemia market opportunity in China, Conterno said.
In Europe, where FibroGen partners with Astellas, roxa in June received a positive opinion from the European Medicines Agency’s drug reviewers. The company expects a final go-ahead from the European Commission this month.
Still, in the case of an FDA rejection, Conterno acknowledged on the call that FibroGen would have to “basically reassess our priorities and reallocate our resources and significantly decrease expenses.”
As Porges sees it, a major restructuring should happen in the next six months to preserve capital and allocate funding to pivotal trials of its pancreatic cancer candidate pamrevlumab, a potential first-in-class antibody against connective tissue growth factor, or CTGF. The company recently modified the drug’s phase 3 trial design to enable a potential accelerated approval pathway with the FDA.
AstraZeneca: FDA Calls for Extra Clinical Trial on Safety of Roxadustat
AstraZeneca PLC said Wednesday that the U.S. Food and Drug Administration has asked for an extra clinical trial of roxadustat for the treatment of anemia of chronic kidney disease before it can approve the company's new drug application.
The pharmaceutical giant said that it is working with its partner FibroGen Inc. to evaluate the next steps.
AstraZeneca added that the safety and effectiveness of roxadustat has been demonstrated in a Phase 3 program in more than 8,000 patients.
Roxadustat is already approved in a number of countries, including China and Japan, and is under regulatory review in the European Union and other jurisdictions, the company said.