Bio­gen spells out re­mark­able ef­fi­ca­cy da­ta in Alzheimer's for ad­u­canum­ab, but safe­ty threat per­sists

Saman­tha Budd Hae­ber­lein, Bio­gen

Shares of Bio­gen jumped Thurs­day af­ter­noon af­ter an up­dat­ed as­sess­ment of the re­mark­ably pos­i­tive da­ta they’ve been col­lect­ing from the PRIME study of their Alzheimer’s drug hope­ful ad­u­canum­ab was leaked among in­vestors and then quick­ly spread on­line.

Aside from the ker­fuf­fle over how the da­ta first be­gan to sur­face, a close look at the full set of re­sults re­vealed a sur­pris­ing­ly pos­i­tive read­out that will help ig­nite re­newed en­thu­si­asm for Bio­gen’s prospects in what is per­haps the tough­est field in R&D — though a big safe­ty is­sue re­mains a key con­cern.

Look­ing over the da­ta from 196 pa­tients, in­ves­ti­ga­tors re­port­ed that they tracked sig­nif­i­cant de­creas­es in amy­loid plaque bur­den in the brains of pa­tients tak­ing a titrat­ed 10 mg dose of the drug “dur­ing 12 months of treat­ment in ApoE ε4-pos­i­tive pa­tients with pro­dro­mal or mild AD com­pared with place­bo.” And they linked that to a clear and sig­nif­i­cant slow­ing of the dis­ease.

Bio­gen’s shares end­ed up 1.5% at the close, af­ter bounc­ing up and down as the da­ta were passed around. In pre-mar­ket trad­ing shares spiked 3.75%.

In­ves­ti­ga­tors were able to track a slow­ing in the de­cline among pa­tients tak­ing a titrat­ed dose of ad­u­canum­ab. And the most com­mon ad­verse ef­fect, ARIA, “ap­peared” to be re­duced among the titrat­ed drug arm com­pared to the high­er fixed dose among pa­tients with the ApoE4 gene, which may pre­dis­pose them to the dis­ease.

The slow­ing in the Clin­i­cal De­men­tia Rat­ing-Sum of Box­es (CDR-SB, which mea­sures cog­ni­tive and func­tion­al per­for­mance) scale was sta­tis­ti­cal­ly sig­nif­i­cant in the titrat­ed arm com­pared to the place­bo group. And the in­ves­ti­ga­tors say they felt the da­ta they had gath­ered sup­port­ed the de­sign of their Phase III study, which puts this drug to the piv­otal test.

There ap­peared to be a clear dose re­sponse to the drug, which is what in­ves­ti­ga­tors like to see.

In a re­lease is­sued late Thurs­day, Bio­gen spelled out the changes in both the CDR-SB and MMSE mea­sures, break­ing out the scores by dos­es com­pared to a place­bo. For the CDR-SB Group, the place­bo arm wors­ened by an av­er­age of 1.89 points at 54 points. That was close to the 1.69 point drop for the 1 mg group, but far worse than the 0.70 in the titra­tion arm. The 10 mg group had the best score of 0.63.

On the MMSE score, the place­bo arm wors­ened an av­er­age of 2.45 points, but that dropped to 0.55 in the 10 mg arm and 1.00 in the titra­tion arm.

ARIA, though, is clear­ly a per­sis­tent prob­lem. The in­ci­dence of ARIA-E in ApoE4 car­ri­ers in the fixed-dose arms was 5 per­cent in the 1 mg/kg and 3 mg/kg arms, 43 per­cent in the 6 mg/kg arm and 55 per­cent in the 10 mg/kg arm. The in­ci­dence of ARIA-E in ApoE4 car­ri­ers in the titra­tion arm was 35 per­cent.

Bri­an Sko­r­ney, Baird an­a­lyst

This is some of the most en­cour­ag­ing da­ta the Alzheimer’s field has seen in years, leav­ing ad­u­canum­ab as one of the top prospects now in late-stage de­vel­op­ment. While much more safe­ty and ef­fi­ca­cy da­ta re­main to be gath­ered in piv­otal stud­ies, its suc­cess at this stage marks a po­ten­tial turn­ing point, which could be rich­ly re­ward­ed by a mar­ket des­per­ate for an ef­fec­tive ther­a­py, es­pe­cial­ly so soon af­ter Eli Lily’s so­la flopped.

“Both ab­stracts high­light sig­nif­i­cant de­clines in plaque bur­den and as­so­ci­at­ed ben­e­fits in terms of the rate of clin­i­cal de­cline, with the titra­tion co­hort show­ing a stat sig ben­e­fit on CDR-SB com­pared to place­bo at 12 months,” not­ed Bri­an Sko­r­ney, who was en­cour­aged by the ex­ten­sion da­ta. He added:

 Of the 165/196 pa­tients in the PRIME study on a fixed dose, 91 were evalu­able out to 24 months. Pa­tients switched from place­bo to ad­u­canum­ab did show de­clines in plaque bur­den and slow­er rates of cog­ni­tive/func­tion­al de­cline. Pa­tients in the 10mg/kg and 6mg/kg dose groups re­main­ing on drug saw con­tin­ued ben­e­fit out to 24 months and an even more sig­nif­i­cant re­sponse than those who were switched on­to drug af­ter place­bo. There were no new cas­es of ARIA for those con­tin­u­ing on ad­u­canum­ab in the LTE. The one year fol­low up should be in­ter­pret­ed with cau­tion as pa­tients know they are on treat­ment and the clin­i­cal mea­sure­ments are sub­ject to high vari­abil­i­ty.

Ad­u­canum­ab is a crit­i­cal­ly im­por­tant drug for Bio­gen, which has ex­pe­ri­enced a se­ries of pipeline ups and downs as its block­buster Tec­fidera has be­gun to wane on the big mul­ti­ple scle­ro­sis mar­ket.

“The da­ta at CTAD sup­port the pos­i­tive re­sults we have seen in our Phase 1b study of ad­u­canum­ab, and they pro­vide in­sight in­to the ob­served ef­fects in pa­tients treat­ed for up to two years,” said Saman­tha Budd Hae­ber­lein, vice pres­i­dent, clin­i­cal de­vel­op­ment at Bio­gen. “We are com­mit­ted to ad­vanc­ing our glob­al Phase 3 pro­gram for ad­u­canum­ab as well as the sci­en­tif­ic un­der­stand­ing of Alzheimer’s dis­ease so we can help iden­ti­fy a treat­ment for the many peo­ple af­fect­ed by this ter­ri­ble dis­ease.”

https://twit­ter.com/Arm­strong­Drew/sta­tus/806952994855997440

Con­quer­ing a silent killer: HDV and Eiger Bio­Phar­ma­ceu­ti­cals

Hepatitis delta, also known as hepatitis D, is a liver infection caused by the hepatitis delta virus (HDV) that results in the most severe form of human viral hepatitis for which there is no approved therapy.

HDV is a single-stranded, circular RNA virus that requires the envelope protein (HBsAg) of the hepatitis B virus (HBV) for its own assembly. As a result, hepatitis delta virus (HDV) infection occurs only as a co-infection in individuals infected with HBV. However, HDV/HBV co-infections lead to more serious liver disease than HBV infection alone. HDV is associated with faster progression to liver fibrosis (progressing to cirrhosis in about 80% of individuals in 5-10 years), increased risk of liver cancer, and early decompensated cirrhosis and liver failure.
HDV is the most severe form of viral hepatitis with no approved treatment.
Approved nucleos(t)ide treatments for HBV only suppress HBV DNA, do not appreciably impact HBsAg and have no impact on HDV. Investigational agents in development for HBV target multiple new mechanisms. Aspirations are high, but a functional cure for HBV has not been achieved nor is one anticipated in the forseeable future. Without clearance of HBsAg, anti-HBV investigational treatments are not expected to impact the deadly course of HDV infection anytime soon.

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Preliminary data on two patients with blood disorders that have been administered with Vertex and partner CRISPR Therapeutics’ gene-editing therapy suggest the technology is safe and effective, marking the first instance of the benefit of the use of CRISPR/Cas9 technology in humans suffering from disease.

Patients in these phase I/II studies give up peripheral blood from which hematopoietic stem and progenitor cells are isolated. The cells are tinkered with using CRISPR/Cas9 technology, and the edited cells — CTX001 — are infused back into the patient via a stem cell transplant. The objective of CTX001 is to fix the errant hemoglobin gene in patents with two blood disorders: beta-thalassemia and sickle cell disease, by unleashing the production of fetal hemoglobin.

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UP­DAT­ED: Make that 2 ap­proved RNAi drugs at Al­ny­lam af­ter the FDA of­fers a speedy OK on ul­tra-rare dis­ease drug

Seventeen years into the game, Alnylam’s pivot into commercial operations is picking up speed.
The bellwether biotech $ALNY has nabbed their second FDA OK for an RNAi drug, this time for givosiran, the only therapy now approved for acute hepatic porphyria. This second approval came months ahead of the February deadline — even after winning priority review following their ‘breakthrough’ title earlier.
AHP is an extremely rare disease, with some 3,000 patients in Europe and the US, not all diagnosed, and analysts have projected peak revenue of $600 million to $700 million a year. The drug will be sold as Givlaari.

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David Ricks. Eli Lilly

Eli Lil­ly touts $400M man­u­fac­tur­ing ex­pan­sion, 100 new jobs to much fan­fare in In­di­anapo­lis — even though it's been chop­ping staff

Eli Lilly is pouring in $400 million to beef up manufacturing facilities at its home base of Indianapolis. The investment, which was lauded by the city’s mayor, is expected to create 100 new jobs.

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Am­gen chops 172 more staffers in R&D, op­er­a­tions and sales amid neu­ro­science ex­it, rev­enue down­turn

Neuroscience wasn’t the only unit that’s being hit by a reorganization underway at Amgen. As well as axing 149 employees in its Cambridge office, the company has disclosed that 172 others nationwide, including some from its Thousand Oaks, CA headquarters, are being let go.

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Stephen Hahn (via Senate HELP Committee)

Stephen Hahn gets through Sen­ate’s soft­ball job in­ter­view — but most­ly plays dodge­ball on the is­sues fac­ing the FDA

Anyone looking for fresh insights on what kind of FDA commissioner Stephen Hahn will be got precious few clues during Wednesday’s Senate hearing on the nomination.

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Op­di­vo/Yer­voy com­bo for melanoma fails in key pa­tient pop­u­la­tion

Bristol-Myers Squibb’s efforts to expand their checkpoint inhibitor combination have run into another recalcitrant cancer.

The NJ-based pharma announced that a combination of Yervoy and Opdivo didn’t beat out Opdivo alone in patients with resected high-risk melanoma who had very low levels of PD-L1. The drug combo couldn’t improve recurrence-free survival in these post-surgery patients.

Ver­tex's stel­lar quar­ter car­ries on with French re­im­burse­ment deal

Vertex’s golden quarter just got brighter. About a month after the US drugmaker finally clinched a deal with UK authorities to cover its slate of cystic fibrosis (CF) drugs following years of protracted negotiations, the company on Wednesday secured a deal with France for its CF therapy, Orkambi.

After the UK, France has one of the largest CF populations outside the United States. Achieving French reimbursement unlocks an ~7000-patient CF population, around ~2500-3000 of which will likely be eligible to receive (and be reimbursed for) Orkambi, Stifel’s Paul Matteis wrote in a note.

Nello Mainolfi, Kymera via Youtube

Kymera hands the helm to No­var­tis vet — and found­ing CSO — Nel­lo Main­olfi

Kymera Therapeutics is turning to a co-founder to run the company.
The protein degradation specialist with a deep-pocket syndicate behind them has opted to give the helm officially to Nello Mainolfi. The new CEO is a veteran of the Novartis Institutes for Biomedical Research. He joined Atlas Venture in their entrepreneur-in-residence program and helped launch Kymera as the CSO three years ago with Atlas’ Bruce Booth.
The boast at Kymera is that they’re angling to create a new class of protein degraders, a popular field where there’s been a variety of startups. One of its chief advocates is NIBR head Jay Bradner, who launched C4 just ahead of joining Novartis, where he’s also been doing new work in the field.