Relay's targeted cancer drug may be safer than rivals. But more effective?

 Relay Therapeutics, a six-year-old biotech trying to make better drugs by studying how the proteins they target move, on Friday released the first clinical trial results for its most advanced treatment.

On one score at least, Relay seems to have had some success. The company's drug, a cancer medicine known as RLY-400, appears less toxic than its would-be competitors. But RLY-4008 still caused other side effects, particularly at a more frequent dosing schedule that's been discontinued. And the preliminary data disclosed by Relay, while promising, are too early to prove whether the drug is more effective.

The results are from four dozen patients in a Phase 1 trial and some uncertainty is to be expected as Relay figures out the best dose of its drug. But the data are nonetheless a test case of the company's pitch that its technology can give it a leg up over other drug developers.

Founded in 2015, Relay aims to pair established drug-hunting techniques with simulations of how proteins move and shape-shift — valuable information for designing medicines. The company's methods borrow from, and extend the structure-based approach Vertex Pharmaceuticals first took to drug design and popularized decades ago. (Mark Murcko, a veteran Vertex researcher and executive, was one of Relay's founders.)

In the case of RLY-4008, Relay used protein motion models to identify key differences in the movements of two related proteins called FGFR1 and FGFR2, the latter of which is frequently mutated in certain cancers. Though the two are seemingly identical to each other when frozen in crystal, FGFR1 has a segment that extends outward from the protein more often than FGFR2.

Relay scientists used that discovery to design RLY-4008 to target only FGFR2 and, in theory, avoid FGFR1 and other related proteins.

Three FGFR inhibitors are already approved: Johnson & Johnson's Balversa in bladder cancer as well as Incyte's Pemazyre and QED Therapeutics' Truseltiq in a type of bile duct cancer called cholangiocarcinoma.

But all three can inhibit FGFR1, which is needed by the kidneys to reabsorb phosphate from the blood. By blocking FGFR1, the drugs commonly cause high phosphate levels, which in testing led patients to pause or stop treatment.

Relay's results were different. In the Phase 1 study, which mostly included patients with cholangiocarcinoma, the rate of hyperphosphatemia was much lower than observed in clinical trials of Pemazyre, Trulsetiq and an experimental FGFR inhibitor called futibatinib.

"Despite hammering FGFR2, we're seeing a rate of hyperphosphatemia that's quite low and clinically irrelevant," said Don Bergstrom, head of R&D at Relay, in an interview. "It's transient and doesn't require medical management."

Treatment with RLY-4008 also led to much lower rates of diarrhea, another common side effect with FGFR inhibitors.

Yet while rates of both side effects were lower, they still occurred with RLY-4008, particularly when the drug was taken twice a day. Relay has stopped further testing of that dosing in favor of once daily, but the data could suggest RLY-4008 is still inhibiting other FGFR proteins, just much less readily.

"While at some of the higher doses we may have been starting to maybe tickle FGFR1 a little bit, I think what this is telling us is that really, especially in the once-daily dosing schedule, we're seeing minimal engagement of FGFR1," explained Bergstrom.

RLY-4008 also caused a number of other notable side effects, including mouth sores, nail toxicities and a skin condition associated with some cancer treatments called hand-foot syndrome. All were reported in testing of the other FGFR inhibitors.

Relay's goal isn't just to design a safer version of available drugs, though. The company aims to prove RLY-4008 is more effective as well.

On that measure, Relay had some promising data to share, but overall results were limited by small sample sizes and follow-up that's still continuing.

Among six patients with cholangiocarcinoma who hadn't previously received FGFR-targeted drugs, treatment with RLY-4008 shrank tumors in three, including one whose tumor was then surgically removed.(Another of the responses, however, was from the twice-daily regimen that Relay has discontinued.)

RLY-4008 was also able to shrink tumors in patients who were previously treated with an FGFR blocker and had developed resistance to treatment, although none were judged to have a confirmed response yet.

Outside of bile duct cancer, Relay observed a partial response in a trial participant with breast cancer who had a different type of FGFR mutation.

"I think this now our beachhead for moving beyond cholangiocarcinoma and moving more broadly into patients with FGFR2-altered tumors," said Bergstrom.

Relay expects to choose a dose for Phase 2 testing by the end of the year, and will disclose updated results early in 2022.

Shares in Relay, which is currently worth nearly $3 billion, remained halted on Friday, although the stock fell by more than 10% on Thursday before the data were released. Results were presented at the virtual AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference.

https://www.biopharmadive.com/news/relay-therapeutics-fgfr-cancer-study-results/607885/

CMS: Medicare Advantage plans with 4 or more stars skyrocket in 2022 v. 2021

 Nearly 70% of Medicare Advantage (MA) plans that offer prescription drug coverage will have a star rating of four or more stars in 2022, a massive increase from 49% of plans in 2021, new federal data show.

The data on MA and Part D star ratings, released Friday by the Centers for Medicare & Medicaid Services, come ahead of Medicare open enrollment that kicks off Oct. 15.

“The Medicare Advantage and Part D Star Ratings are important tools in the toolbox for beneficiaries to use as they consider Medicare coverage options,” CMS Administrator Chiquita Brooks-LaSure said in a statement. “CMS’ annual ratings deliver meaningful information about the quality of each plan to help people with Medicare make informed healthcare decisions.”

MA plans get a star rating from one to five each year based on their performance on several measures that include patient satisfaction and screenings. Star ratings typically are calculated based on the prior year, so the 2022 ratings are based on data from this year.

“While adjustments were made for the 2022 star ratings due to the possible impact of the COVID-19 pandemic, this also reflects improvements in sponsors’ scores on several measures,” CMS said.

The increase in plans with higher star ratings is likely to drive more Medicare spending into the MA program.

MA plans get bonuses for reaching quality ratings of four or more stars.

An analysis from the Kaiser Family Foundation discovered that the annual bonuses to MA plans quadrupled from 2015 to 2021, with plans getting $11.6 billion in bonuses this year compared to $3 billion in 2015. Unrated MA plans are also eligible to receive a bonus.

“The rise in bonus payments is due to both an increase in the number of plans receiving bonuses, and an increase in the number of enrollees in these plans,” Kaiser’s analysis said.

CMS reported Friday that approximately 90% of people are currently in an MA plan that will have four or more stars in 2022.

Spending on MA plans has outpaced traditional Medicare. A separate Kaiser analysis found that MA payments increased federal spending by $7 billion in 2019, driven primarily by higher rebates and benchmarks used to determine payments to an MA plan. Those benchmarks can be increased if a plan’s star ratings also increase.

https://www.fiercehealthcare.com/payer/cms-medicare-advantage-plans-four-or-more-stars-skyrocket-2022-compared-to-2021

Merck's COVID 'Super Drug' Poses Serious Health Risks, Scientists Warn

 As it turns out, all the scientists and doctors who insisted that Merck's "revolutionary" COVID drug molnupiravir is extremely safe weren't faithfully adhering to "the science" after all. Because according to a report published Thursday by Barron's, some scientists are worried that the drug - which purportedly cut hospitalizations in half during a study that was cut short - could cause cancer or birth defects.

So much for having a "strong safety profile," as Dr. Scott Gottlieb claimed in an interview on the day Merck first publicized the research.

It's perfectly understandable why Merck might choose to play down this safety risk: assuming it's approved, the drug is widely expected to be one of "the most lucrative drugs ever" - which is one reason why Merck's shares soared into double-digit territory after the announcement.

As we reported earlier this week, Merck and its "partner" Ridgeback Biotherapeutics will profit immensely by charging customers up to 40x what it costs to make the drug, which Ridgeback originally licensed from Emory University for an "undisclosed sum". The drug was developed with funding from the federal government.

According to Barron's, some scientists who have studied the drug believe that its method of suppressing the virus could potentially run amok within the body.

Some scientists who have studied the drug warn, however, that the method it uses to kill the virus that causes Covid-19 carries potential dangers that could limit the drug’s usefulness.

Molnupiravir works by incorporating itself into the genetic material of the virus, and then causing a huge number of mutations as the virus replicates, effectively killing it. In some lab tests, the drug has also shown the ability to integrate into the genetic material of mammalian cells, causing mutations as those cells replicate.

If that were to happen in the cells of a patient being treated with molnupiravir, it could theoretically lead to cancer or birth defects.

In particular, Raymond Schinazi, a professor of pediatrics and the director of biochemical pharmacology at Emory who studied the drug while it was being developed, and published a number of papers on NHC, the compound that's the active ingredient in the drug. He published a paper that showed the drug can produce a reaction like the one described above, and insisted it shouldn't be given to young people - especially pregnant women - without more data.

Schinazi told Barron’s that he did not believe that molnupiravir should be given to pregnant women, or to young people of reproductive age, until more data is available. Merck’s trials of molnupiravir have excluded pregnant women; the scientists running the trial asked male participants to “abstain from heterosexual intercourse” while taking the drug, according to the federal government website that tracks clinical trials.

Barron's even shared a paper published in the Journal of Infectious Diseases in May by Schinazi and scientists at the University of North Carolina which reported that NHC can cause mutations in animal cell cultures in a lab test designed to detect such mutations - something Merck claims it has tested for. The paper's authors concluded that the risks for molnupiravir "may not be zero".

Merck told Barron's that it has run "extensive tests" on animals which it says show that this shouldn't be an issue. "The totality of the data from these studies indicates that molnupiravir is not mutagenic or genotoxic in in-vivo mammalian systems," a Merck spokesman said.

Still, scientists and doctors who have studied NHC say that Merck needs to "be careful," and it's not just Schinazi warning about the drug's potential risks.

Dr. Shuntai Zhou, a scientist at the Swanstrom Lab at UNC, said "there is a concern that this will cause long-term mutation effects, even cancer."

Zhou says that he is certain that the drug will integrate itself into the DNA of mammalian hosts. "Biochemistry won’t lie," he says. "This drug will be incorporated in the DNA."

Merck hasn't yet released any data from its animal studies, but the scientists believe that it would take long-term studies to show that the drug is truly totally safe.

"Proceed with caution and at your own peril," wrote Raymond Schinazi, a professor of pediatrics and the director of the division of biochemical pharmacology at the Emory University School of Medicine, who has studied NHC for decades, in an email to Barron’s.

Analysts are already warning that these questions about the drug's safety suggest the reaction in Merck's shares was a little "overblown", to say the least. Investors apparently were so eager for a new "pandemic panacea" (now that the mRNA jabs have proven to be much less effective than advertised) that they didn't ask too many questions about safety, or even question the paucity of data. One analyst for SVB Leerink Dr. Geoffrey Porges described investors' reaction from Friday as "wishful thinking".

Even once the FDA authorizes the drug, Dr. Porges believes it will come with strict limitations on who can and can't use it. "I think it is effectively going to be a controlled substance", Dr. Porges said, adding that the risks to pregnant women, or women who may soon become pregnant, could present thorny problems for the FDA's advisory committee reviewing the drug.

Given that the safety risks of the drug seem well-documented already, Wall Street's gushing about the drug's prospects - "it really is THAT good", one analyst insisted - seems like an idiotic blunder in retrospect. The product of what one might call "magical thinking".

https://www.zerohedge.com/covid-19/proceed-caution-your-own-peril-mercks-covid-super-drug-poses-serious-health-risks

Solid tumor biotech Aura Biosciences files for a $100 million IPO

 Aura Biosciences, a Phase 2 biotech developing virus-like drug conjugates for ocular and urologic solid tumors, filed on Friday with the SEC to raise up to $100 million in an initial public offering.

Aura's proprietary platform enables the targeting of a broad range of solid tumors using Virus-Like Particles that can be conjugated with drugs or loaded with nucleic acids to create Virus-Like Drug Conjugates (VDCs). AU-011, its first VDC candidate, is being developed for the first line treatment of primary choroidal melanoma, a rare disease with no drugs approved. The company has advanced AU-011 into a Phase 2 dose escalation trial, where it is currently evaluating suprachoroidal administration. Aura plans to present six to twelve month safety and efficacy data from this trial in 2022, and, if favorable, initiate a pivotal trial in the 2H22.

The Cambridge, MA-based company was founded in 2009 and plans to list on the Nasdaq under the symbol AURA. Aura Biosciences filed confidentially on August 10, 2021. Cowen, SVB Leerink, and Evercore ISI are the joint bookrunners on the deal. No pricing terms were disclosed.

Relevant Profile: AURA

https://www.renaissancecapital.com/IPO-Center/News/87025/Solid-tumor-biotech-Aura-Biosciences-files-for-a-$100-million-IPO

Rare disease biotech Entrada Therapeutics files for a $100 million IPO

 Entrada Therapeutics, a preclinical biotech developing therapies for rare neuromuscular diseases, filed on Friday with the SEC to raise up to $100 million in an initial public offering.

Entrada aims to transform the lives of patients by establishing Endosomal Escape Vehicle (EEV) therapeutics as a new class of medicines. EEV therapeutics are comprised of small cyclic peptides that are chemically conjugated to a wide range of specific and active biological therapeutics. The company is initially focused on the development of EEV therapeutics for rare neuromuscular diseases, including Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1. Its most advanced candidate, ENTR-601-44, is being developed for patients with DMD that are exon 44 skipping amenable. Entrada plans to submit an IND application for ENTR-601-44 in 2022.

The Boston, MA-based company was founded in 2016 and plans to list on the Nasdaq under the symbol TRDA. Entrada Therapeutics filed confidentially on August 6, 2021. Goldman Sachs, Cowen, and Evercore ISI are the joint bookrunners on the deal. No pricing terms were disclosed.

Relevant Profile: TRDA

https://www.renaissancecapital.com/IPO-Center/News/87031/Rare-disease-biotech-Entrada-Therapeutics-files-for-a-$100-million-IPO

Germany-listed drug discovery company Evotec files for a $100 million US IPO

 Evotec, which provides drug discovery solutions for the pharmaceutical industry, filed on Friday with the SEC to raise up to $100 million in an initial public offering. The company is currently listed on the Frankfurt Stock Exchange under the symbol EVT, with a market cap of about $7.5 billion.

The company calls itself an industry-leading drug discovery and development partner for the pharmaceutical and biotechnology industry, focused on discovering drug candidates in a wide range of difficult-to-treat diseases. It generates income by charging fees for its services, collecting milestones and royalties, and through equity ownership in biotechs. Evotec states that its pipeline has over 130 assets.

The Hamburg, Germany-based company was founded in 1993 and booked $626 million in revenue for the 12 months ended June 30, 2021. It plans to list on the Nasdaq under the symbol EVO. Evotec filed confidentially on July 9, 2021. BofA Securities, Morgan Stanley, Citi, Jefferies, Cowen, and RBC Capital Markets are the joint bookrunners on the deal. No pricing terms were disclosed.

Relevant Profile: EVO

https://www.renaissancecapital.com/IPO-Center/News/87022/Germany-listed-drug-discovery-company-Evotec-files-for-a-$100-million-US-IP

Orthopedic medical device company Paragon 28 sets terms for $125 million IPO

 Paragon 28, which makes orthopedic implants and medical devices for the foot and ankle, announced terms for its IPO on Friday.

The Englewood, CO-based company plans to raise $125 million by offering 7.8 million shares at a price range of $15 to $17. At the midpoint of the proposed range, Paragon 28 would command a fully diluted market value of $1.3 billion.

Paragon 28 states that it is a leading medical device company exclusively focused on the foot and ankle orthopedic market. Its orthopedic solutions, procedural approaches, and instrumentation cover a wide range of foot and ankle ailments including fracture fixation, hallux valgus (bunions), hammertoe, ankle, progressive collapsing foot deformity (PCFD, or flatfoot), charcot foot, and orthobiologics. The company provides a comprehensive portfolio of solutions that includes surgical implants and disposables, as well as surgical instrumentation, and its suite of surgical solutions comprises 72 product systems and approximately 8,700 SKUs.

Paragon 28 was founded in 2010 and booked $134 million in sales for the 12 months ended June 30, 2021. It plans to list on the NYSE under the symbol FNA. BofA Securities and Piper Sandler are the joint bookrunners on the deal.

Relevant Profile: FNA

https://www.renaissancecapital.com/IPO-Center/News/87016/Orthopedic-medical-device-company-Paragon-28-sets-terms-for-$125-million-IP