Af­ter a crush­ing PhI­II fail­ure, Cy­to­ki­net­ics says its next-gen mus­cle drug is lin­ing up well in PhII — but big chal­lenges loom

For the past 6 months, Cy­to­ki­net­ics $CYTK CEO Robert Blum has been hold­ing things to­geth­er in the wake of a dev­as­tat­ing late-stage dis­as­ter that swept away its lead mus­cle drug. He takes pride in the fact that he was able to sol­dier on with­out gut­ting the staff. And now the biotech and its part­ners at Astel­las are step­ping for­ward with their fol­low-up drug — look­ing to per­suade in­vestors that they can learn from the griev­ous set­back and make a come­back in the field of strength­en­ing pa­tients af­flict­ed by a range of ail­ments.

It’s not go­ing to be easy or quick. In­vestors took a close look at the da­ta to­day and the fall­out end­ed dri­ving the biotech’s stock down 17%.

Robert Blum

Ini­tial­ly cod­ed CK-2127107 and now called relde­sem­tiv — which re­places the de­funct tirasem­tiv — Blum touts the new con­tender as be­ing a safer, bet­ter ap­proach to amp­ing up mus­cles. Tirasem­tiv, he says, was done in by the fact that the drug pen­e­trat­ed the blood brain bar­ri­er,  caus­ing dizzi­ness and lim­it­ing dos­ing. This time around, he says, their next-gen ap­proach won’t have that lim­i­ta­tion.

Now in a line­up of mid-stage stud­ies, in­ves­ti­ga­tors for the com­pa­ny rolled out the first snap­shot of Phase II da­ta for spinal mus­cu­lar at­ro­phy. And the da­ta raise some ques­tions, even as Blum high­lights the dose ef­fect among the 70 pa­tients. 

Not sur­pris­ing­ly, the low 150 mg dose used in the study failed to gen­er­ate a sta­tis­ti­cal­ly sig­nif­i­cant re­sult for a 6-minute walk test — one of the stan­dard end­points avail­able to de­vel­op­ers in the are­na. That’s not un­usu­al in a study like this, which goes in search of ham­mer­ing out the right dose to go in­to a reg­is­tra­tion study. The 450 mg did get to sta­tis­ti­cal sig­nif­i­cance at 4 weeks, and then slipped be­low a sig­nif­i­cant re­sponse at 8 weeks.

Ac­cord­ing to re­searchers, the 450 mg dose of the drug in­creased walk­ing dis­tance by 35.63 me­ters (p= 0.0037) at week four and 24.89 me­ters (with a p val­ue of 0.0584) at week eight rel­a­tive to place­bo. There was al­so a sig­nif­i­cant in­crease in Max­i­mal Ex­pi­ra­to­ry Pres­sure —which mea­sures res­pi­ra­to­ry mus­cles — at the low and high dose at 8 weeks, but nei­ther dose scored un­der the 0.05 mark at 4 weeks, which sug­gests a pos­si­ble im­prove­ment over time.

I asked Blum about the 6-minute test re­sults. Slid­ing ef­fi­ca­cy over a short pe­ri­od like that — a shift al­so seen in the low­er dose arm of the study — could sig­ni­fy that the drug has on­ly a tran­sient ef­fect, which could prove a se­ri­ous threat.

Blum, though, bat­ted it back, in­sist­ing that the down­ward shift was due sole­ly to the small pa­tient pop­u­la­tion in­volved. Re­searchers have the chance to dou­ble up on that dose in a piv­otal study, he adds. And fu­ture work would al­so ex­tend out end­points on ef­fi­ca­cy to 12 weeks.

“That’s with­in the noise of sta­tis­tics this size,” the CEO says. “We don’t see that as a ta­per­ing.”

“This is the first of four such stud­ies,” adds the CEO. “These da­ta lend sup­port for the mech­a­nism and the mol­e­cule. We know relde­sem­tiv is more po­tent, more pen­e­tra­ble in­to mus­cle.”

Re­searchers at Cy­to­ki­net­ics and Astel­las are now fo­cused on ALS, COPD and frailty in the el­der­ly, though they may even­tu­al­ly go down the path of sar­cope­nia as the FDA works on new reg­u­la­to­ry path­ways for ag­ing. This par­tic­u­lar pro­gram, says Blum, isn’t di­rect­ly com­pet­i­tive with the oth­er SMA drugs in the clin­ic, such as the one PTC and Roche are re­port­ing on to­day, or Bio­gen’s pi­o­neer­ing Spin­raza. A drug like theirs can be nice­ly com­ple­men­tary to any oth­er drugs tar­get­ed di­rect­ly at the dis­ease.

Where do they go from here? Blum isn’t talk­ing time­lines yet, as he cau­tious­ly moves for­ward to­ward fi­nal­iz­ing an­oth­er piv­otal tri­al. Fail­ure isn’t go­ing to be an op­tion.

The Big Phar­ma dis­card pile; Lay­offs all around while some biotechs bid farewell; New Roche CEO as­sem­bles top team; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

With earnings seasons in full swing, we’ve listened in on all the calls so you don’t have to. But news is popping up from all corners, so make sure you check out our other updates, too.

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Raymond Stevens, Structure Therapeutics CEO

Be­hind Fri­day's $161M IPO: A star sci­en­tist, GPCR drug dis­cov­ery and a plan to chal­lenge phar­ma in di­a­betes

What does it take to pull off a $161 million biotech IPO these days?

In Structure Therapeutics’ case, it means having a star scientist co-founder paired with the computational drug discovery company Schrödinger, $198 million in private funding from blue-chip investors, almost six years of research work on G protein-coupled receptors and a slate of oral, small-molecule drugs, with an eye on the huge and growing diabetes and weight-loss market.

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Ma­gen­ta halts stem cell work and may sell it­self fol­low­ing pa­tient death, clin­i­cal hold

Magenta Therapeutics said it is halting work on its stem cell transplant drug pipeline and may sell itself, a week after the company reported the death of a patient in an early stage trial of its antibody-drug conjugate.

The Cambridge, MA-based company said it will conduct a “review of strategic alternatives,” and that could include an “acquisition, merger, business combination, or other transaction.”

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Sen. Ron Wyden (D-OR) (Francis Chung/E&E News/Politico via AP Images)

In­fla­tion re­bates in­com­ing: Wyden calls on CMS to move quick­ly as No­var­tis CEO pledges re­ver­sal

Senate Finance Chair Ron Wyden (D-OR) this week sent a letter to the head of the Centers for Medicare & Medicaid Services seeking an update on how and when new inflation-linked rebates will take effect for drugs that see major price spikes.

The newly signed Inflation Reduction Act requires manufacturers to pay a rebate to Medicare when they increase drug prices faster than the rate of inflation.

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Trodelvy notch­es a win in most com­mon form of breast can­cer

Following a promise last year to go “big and fast in breast cancer,” Gilead has secured a win for Trodelvy in the most common form.

The drug was approved to treat HR-positive, HER2-negative breast cancer patients who’ve already received endocrine-based therapy and at least two other systemic therapies for metastatic cancer, Gilead announced on Friday.

Trodelvy won its first indication in metastatic triple-negative breast cancer back in 2020, and has since added urothelial cancer to the list. HR-positive HER2-negative breast cancer accounts for roughly 70% of new breast cancer cases worldwide per year, according to senior VP of oncology clinical development Bill Grossman, and many patients develop resistance to endocrine-based therapies or worsen on chemotherapy.

Sanofi scraps PhI­II tri­al for Prin­cip­ia drug af­ter re­view­ing com­pe­ti­tion

Months after the FDA placed Phase III trials of Sanofi’s BTK inhibitor on hold, the company is winding down one of the studies.

Sanofi reported in its Q4 earnings that the URSA study “was discontinued after careful evaluation of the emerging competitive treatment landscape in” myasthenia gravis, a rare disease that causes muscle weakness.

The Phase III, placebo-controlled trial was testing tolebrutinib in patients with the moderate-to-severe form of the disease. It started in late 2021, according to records on clinicaltrials.gov, and was originally designed to recruit 154 participants who were receiving the standard of care.

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Af­ter 13 years, Ramy Mah­moud steps in­to CEO seat at Opti­nose; Ru­pert Vessey set to ex­it Bris­tol My­ers in Ju­ly

After 13 years as president and COO at Optinose, Ramy Mahmoud has stepped into a new role as its CEO. He is taking the place of Peter Miller, who stepped down earlier this week, though Miller is still staying with the company as a consultant.

In 2010, the two business partners joined Optinose to take it in a new direction, transforming it from a delivery platform to product company. They previously worked together at Johnson & Johnson, when Miller was president at Janssen and Mahmoud headed medical affairs. Miller said after he learned about Optinose, “I did what I always do, which is find people smarter than me to talk with about the idea. And the first person I called was Ramy … and I said, ‘Hey, Ramy, what do you think of this technology?’”

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How to use ex­ter­nal con­trols: FDA spells out think­ing in new draft guid­ance

The use of real-world evidence to inform the FDA’s decision-making continues apace, with the agency releasing new draft guidance yesterday on how sponsors can compare outcomes of trial participants receiving a test treatment with outcomes in a group of people external to the trial.

The practice of externally controlled trials is common, particularly in oncology or other difficult areas where it’s not ethical or feasible to use internal controls.

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The Big Phar­ma axe: Mer­ck cuts chikun­gun­ya vax, Bris­tol My­ers drops Cy­tomX-part­nered pro­gram, and more

As fourth quarter earnings come in, Big Pharmas are disclosing changes to their pipelines during their investor calls, and sometimes more quietly in presentation appendices.

Merck dropped its chikungunya vaccine candidate, which completed a Phase II study. Merck acquired the vaccine through its purchase of Themis Bioscience in 2020. In developing a vaccine for chikungunya, a mosquito-borne virus, Valneva is the frontrunner, as it submitted its vaccine to the FDA at the end of December.

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