#AS­CO21: As­traZeneca takes a swing at J&J and Ab­b­Vie's Im­bru­vi­ca with long-term da­ta from head-to-head tri­al

A year and a half af­ter get­ting its next-gen BTK in­hibitor ap­proved in chron­ic lym­pho­cyt­ic leukemia (CLL), As­traZeneca is back with long-term da­ta that sug­gest the drug stands a fight­ing chance against J&J and Ab­b­Vie’s first gen­er­a­tion block­buster Im­bru­vi­ca.

At a me­di­an fol­low-up of 40.9 months, Calquence matched Im­bru­vi­ca for a me­di­an pro­gres­sion-free sur­vival of 38.4 months in pa­tients who had pre­vi­ous­ly been treat­ed for CLL, As­traZeneca an­nounced at AS­CO. But when it came to car­diac events, Calquence best­ed its long­stand­ing ri­val, with a 9.4% in­ci­dence of all-grade atri­al fib­ril­la­tion, com­pared to a 16% rate in the Im­bru­vi­ca arm (p= 0.02). Atri­al fib­ril­la­tion is an ir­reg­u­lar heart­beat that can lead to stroke or heart fail­ure.

The news — which comes as As­traZeneca strug­gles in vac­cines — rep­re­sents an­oth­er win in Pas­cal So­ri­ot’s ef­fort to es­tab­lish the com­pa­ny as a leader in on­col­o­gy.

“Car­diac ad­verse events are an im­por­tant con­sid­er­a­tion for treat­ing chron­ic lym­pho­cyt­ic leukemia pa­tients with Bru­ton’s ty­ro­sine ki­nase in­hibitors be­cause they can pro­duce sig­nif­i­cant mor­bid­i­ty in some cas­es and al­so lead pa­tients to dis­con­tin­ue treat­ment,” John Byrd, lead in­ves­ti­ga­tor of As­traZeneca’s EL­E­VATE-RR tri­al, said in a state­ment.

CLL is the most com­mon type of leukemia in adults, with more than 21,000 new cas­es re­port­ed in the US so far this year. In pa­tients with the dis­ease, too many blood stem cells in the bone mar­row be­come ab­nor­mal lym­pho­cytes, which have dif­fi­cul­ty fight­ing in­fec­tions. As the num­ber of ab­nor­mal cells grows, there’s less room for healthy white and red blood cells and platelets, As­traZeneca said.

Calquence was ap­proved for CLL back in No­vem­ber 2019, both as a monother­a­py in sec­ond-line pa­tients and as a com­bi­na­tion treat­ment with Roche’s Gazy­va in front­line pa­tients. But the El­e­vate-RR tri­al is the first to com­pare the two BTK in­hibitors head-to-head in CLL, and should help As­traZeneca carve out a space in the mar­ket.

Calquence bagged $522 mil­lion in sales last year, com­pared to Im­bru­vi­ca’s glob­al sales of $5.3 bil­lion.

El­e­vate-RR en­rolled 533 pa­tients with a form of CLL that doesn’t re­spond to treat­ments like chemother­a­py. In ad­di­tion to low­er in­ci­dence of atri­al fib­ril­la­tion, As­traZeneca says those in the Calquence arm al­so saw a less­er fre­quen­cy of oth­er side ef­fects, in­clud­ing bleed­ing events, hy­per­ten­sion and in­fec­tions.

“The safe­ty and tol­er­a­bil­i­ty of Calquence in El­e­vate-RR was con­sis­tent with the known pro­file of Calquence,” the com­pa­ny said in a state­ment.

In the Calquence arm, ad­verse events led 14.7% of pa­tients to dis­con­tin­ue the treat­ment, ver­sus 21.3% of pa­tients in the Im­bru­vi­ca arm. All-grade car­diac events were seen in 24.1% of Calquence pa­tients and 30% of Im­bru­vi­ca pa­tients. All-grade bleed­ing events were record­ed in 38% of Calquence pa­tients ver­sus 51.3% of Im­bru­vi­ca pa­tients. Hy­per­ten­sion was seen in 9.4% and 23.2% of pa­tients in the re­spec­tive arms. And all-grade in­fec­tions were seen in 78.2% ver­sus 81.4% of the pa­tients.

How­ev­er, a greater num­ber of pa­tients in the Calquence arm ex­pe­ri­enced sec­ond pri­ma­ry ma­lig­nan­cies ex­clud­ing non-melanoma skin can­cer (9% ver­sus 7.6% in the Im­bru­vi­ca arm).

As­traZeneca al­so read out four-year da­ta from its Phase III El­e­vate-TN tri­al, in which Calquence “con­tin­ued to show a strong PFS ben­e­fit” as a com­bi­na­tion ther­a­py or monother­a­py in pre­vi­ous­ly un­treat­ed CLL pa­tients, the com­pa­ny said.

Af­ter a me­di­an fol­low-up of 46.9 months, Calquence and Gazy­va re­duced pa­tients’ risk of dis­ease pro­gres­sion or death by 90% com­pared to Gazvya and the chemother­a­py chlo­ram­bu­cil, As­traZeneca said. As a monother­a­py, Calquence re­duced the risk of dis­ease pro­gres­sion or death by 81%, ac­cord­ing to the da­ta. Me­di­an pro­gres­sion-free sur­vival wasn’t met in ei­ther arm at the four-year fol­low-up.

Ac­cord­ing to As­traZeneca, es­ti­mat­ed PFS rates for the com­bi­na­tion ther­a­py and monother­a­py are 87% and 78%, re­spec­tive­ly, com­pared to 25% for chlo­ram­bu­cil plus Gazy­va.

“Tol­er­a­bil­i­ty is a crit­i­cal fac­tor in treat­ing pa­tients with chron­ic lym­pho­cyt­ic leukemia who of­ten re­main on med­i­cines for many years and ex­pe­ri­ence mul­ti­ple co­mor­bidi­ties,” Dave Fredrick­son, ex­ec­u­tive VP of As­traZeneca’s on­col­o­gy busi­ness unit, said in a state­ment.

Calquence and Im­bru­vi­ca could soon have some new com­peti­tors, in­clud­ing BeiGene’s Brukin­sa, which demon­strat­ed a “sta­tis­ti­cal­ly sig­nif­i­cant low­er risk of atri­al fib­ril­la­tion or flut­ter” in a head-to-head tri­al with Im­bru­vi­ca back in April. And back in De­cem­ber, Eli Lil­ly said it would but its own BTK in­hibitor LOXO-305 against Im­bru­vi­ca in two head-to-head stud­ies.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

Bio­gen hit by ALS set­back with PhI­II fail­ure for tofersen — but fol­lows a fa­mil­iar strat­e­gy high­light­ing the pos­i­tive

Patients and analysts waiting to hear Sunday how Biogen’s SOD1-ALS drug tofersen fared in Phase III didn’t have to wait long for the top-line result they were all waiting for. The drug failed the primary endpoint on significantly improving the functional and neurologic decline of patients over 28 weeks as well as the extension period for continued observation.

In fact, there was very little difference in response.

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UP­DAT­ED: Boehringer nabs FDA's first in­ter­change­abil­i­ty des­ig­na­tion for its Hu­mi­ra com­peti­tor — but will it mat­ter?

The FDA late Friday awarded Boehringer Ingelheim the first interchangeability designation for its Humira biosimilar Cyltezo, meaning that when it launches in July 2023, pharmacists will be able to automatically substitute the Boehringer’s version for AbbVie’s mega-blockbuster without a doctor’s input.

The designation will likely give Boehringer, which first won approval for Cyltezo in 2017, the leg up on a crowded field of Humira competitors.

Reshma Kewalramani, Vertex CEO (YouTube)

Ver­tex gets much-need­ed win with ‘ex­tra­or­di­nary’ first pa­tient re­sults on po­ten­tial di­a­betes cure

Vertex said Monday that the first patient dosed with its cell therapy for type 1 diabetes saw their need for insulin injections vanish almost entirely, a key early step in the decades-long effort to develop a curative treatment for the chronic disease.

The patient, who had suffered five potentially life-threatening hypoglycemic — or low blood sugar — episodes in the year before the therapy, was injected with synthetic insulin-producing cells. After 90 days, the patient’s new cells produced insulin steadily and ramped up their insulin production after a meal like normal cells do, as measured by a standard biomarker for insulin production.

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No­var­tis de­vel­op­ment chief John Tsai: 'We go deep in the new plat­form­s'

During our recent European Biopharma Summit, I talked with Novartis development chief John Tsai about his experiences over the 3-plus years he’s been at the pharma giant. You can read the transcript below or listen to the exchange in the link above.

John Carroll: I followed your career for quite some time. You’ve had more than 20 years in big pharma R&D and you’ve obviously seen quite a lot. I really was curious about what it was like for you three and a half years ago when you took over as R&D chief at Novartis. Obviously a big move, a lot of changes. You went to work for the former R&D chief of Novartis, Vas Narasimhan, who had his own track record there. So what was the biggest adjustment when you went into this position?

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Susan Galbraith, Executive VP, Oncology R&D, AstraZeneca

As­traZeneca on­col­o­gy R&D chief Su­san Gal­braith: 'Y­ou're go­ing to need or­thog­o­nal com­bi­na­tion­s'


Earlier in the week we broadcast our 4th annual European Biopharma Summit with a great lineup of top execs. One of the one-on-one conversations I set up was with Susan Galbraith, the oncology research chief at AstraZeneca. In a wide-ranging discussion, Galbraith reviewed the cancer drug pipeline and key trends influencing development work at the pharma giant. You can watch the video, above, or stick with the script below. — JC

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Two drug­mak­ers hit with PDU­FA date de­lays from FDA amid back­log of in­spec­tions

As the FDA is weighed down with more and more pandemic responsibilities, the agency is beginning to miss PDUFA dates with more frequency too. Two different companies on Monday said they received notices that the FDA has not completed their drug reviews on time.

The review of an NDA for Avadel Pharmaceuticals’ candidate treatment for narcolepsy is not coming this month, the company said, and the review of UCB’s BLA for bimekizumab, used to treat moderate to severe plaque psoriasis, will miss its target date as well.

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Terrie Curran, Phathom CEO (Credit: Arcutis)

Phath­om's old Take­da drug bests Pre­vacid in a PhI­II GI tri­al. Next stop? The FDA

There’s no time for rest in biopharma — at least not at Phathom Pharmaceuticals. Just over a month after submitting two NDAs for its lead acid-fighter vonoprazan, the biotech is already lining up a third, and collecting an extra $50 million to push things along.

Vonoprazan met its primary non-inferiority endpoints in a Phase III study comparing it to standard-of-care Prevacid in a type of gastroesophageal reflux disease (GERD) called erosive esophagitis (EE). It also proved superior to the popular heartburn drug by multiple measures, including healing rate and maintenance of healing.

Thomas Lingelbach, Valneva CEO

Small biotech says its Covid-19 vac­cine spurs more an­ti­bod­ies than As­traZeneca’s. Will sup­ply deals come now?

In a first, a small runner-up vaccine developer says its own Covid-19 jab has induced “superior neutralizing antibody titer levels” over AstraZeneca’s AZD1222 when pitted head-to-head in a Phase III trial.

That and non-inferiority in seroconversion rate were the co-primary endpoints of the trial, which recruited 4,012 adult volunteers across the UK.

But on the exploratory endpoint of Covid-19 case counts, Valneva notes that both treatment groups saw a similar number of infections.