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Saturday, January 8, 2022

10 clinical trials to watch in the first half of 2022

 One year ago, the biotechnology sector was in the middle of a record run. The successful development of coronavirus vaccines and drugs had helped slow the pandemic and propelled investment into new companies going public at a historic rate. Biotech stock indexes traded at all-time highs.

But that momentum quickly vanished. Clinical and regulatory setbacks, as well as the prospect of drug price reform in the U.S., weighed on companies large and small, driving down stock prices and opening a gulf between the industry's performance and the broader market's. Newly public biotechs struggled to keep their footing, with nearly 80% of the 2021 IPO class trading below their offering prices, according to data from BioPharma Dive.

Positive clinical trial results — events that companies can use to sway investors, cut deals and raise cash — could help turn things around. And multiple opportunities lie ahead, with key studies in breast cancer, cystic fibrosis and ulcerative colitis set to read out in the first half of the year. Here are 10 to watch:

COMPANY:
 
Pfizer, Arena Pharmaceuticals
DISEASE:
 
Ulcerative colitis
TREATMENT TYPE:
 
Small molecule
WHY IT'S IMPORTANT:

Pfizer's $7 billion buyout of Arena, one of the sector's largest acquisitions of 2021, was largely based on the promise of a single drug known as etrasimod. After a disappointing past selling an obesity drug, Arena had rebuilt itself around the medicine, which showed early promise in several inflammatory diseases. Etrasimod works the same way as Zeposia, once the crown jewel of Celgene's acquisition of Receptos and now sold by Bristol Myers Squibb.

Pfizer gambled on Arena on the belief that its drug is better and did so — to the surprise of some Wall Street analysts — before key clinical trial results were available to potentially prove out that hypothesis. Those results will emerge this year, beginning with a pair of studies testing etrasimod in ulcerative colitis.

Pfizer executives revealed on a recent conference call that they had already looked at blinded data from two studies, known as Elevate 12 and Elevate 52, and made the deal assuming etrasimod will succeed. (Results for Elevate 12 could be ready first, according to a federal clinical trials database).

Pfizer is banking on such an outcome to boost its business treating inflammatory diseases, an area where its drugs Xeljanz and abrocitinib have been slowed by safety concerns.

COMPANIES:
 
Sanofi, GlaxoSmithKline
DISEASE:
 
COVID-19
TREATMENT TYPE:
 
Protein vaccine
TRIAL:
 
WHY IT'S IMPORTANT:

The coronavirus pandemic has shifted since 2020, when Sanofi and GlaxoSmithKline partnered to develop a COVID-19 shot. The original coronavirus strain gave way to more elusive variants that are harder targets for the vaccines developed by Moderna, partners Pfizer and BioNTech and others. Boosters, meanwhile, have grown in importance, as they've proved the best defense against the fast-spreading omicron variant and the waning of vaccine protection.

Those factors have left Sanofi and GSK, now several times delayed in their vaccine research, with a potential role to play in 2022 and beyond. In December, the two reported their shot can significantly boost levels of virus-fighting antibodies in people who had previously received any of the four most widely used vaccines. But they can't file for authorization until proving their vaccine can prevent COVID-19 in a large clinical trial, a test that has become harder to complete as more people are vaccinated or infected.

Sanofi and GSK expect to report results from their study in early 2022. If positive, their vaccine, which relies on well-established technologies, could be helpful in places where other shots aren't widely available.

COMPANY:
 
Roche
DISEASE:
 
Alzheimer's
TREATMENT TYPE:
 
Antibody
TRIALS:
 
WHY IT'S IMPORTANT:

Does Aduhelm, the first new Alzheimer's drug in decades, actually slow the mental and physical deterioration caused by the disease? Doctors, experts and even the Food and Drug Administration's own reviewers haven't agreed, fueling a debate that's made the agency's decision to approve the drug among the most controversial in its history.

Faced with conflicting clinical trial data, the FDA chose to clear Aduhelm based on how it is thought to work, elevating a long-debated and unproven disease hypothesis in the process. Over the course of 2022, study results from Roche and Eisai could offer supporting evidence for Aduhelm, its developer Biogen and the FDA, or throw the drug's approval further into doubt.

Aduhelm, Roche's gantenerumab and Eisai's lecanemab all work by targeting clumps of a protein in the brain known as amyloid. A long list of predecessors — also aimed at amyloid, in one fashion or another — have failed in clinical trials over the past decade.

Hopes are higher, though, that gantenerumab and lecanemab could show a benefit, based on the type of amyloid clump they target and more carefully tailored study designs. (Gantenerumab fell short in a previous study, but is being reevaluated at a higher dose.)

Already, Eisai — Biogen's development partner on Aduhelm — has applied for accelerated approval of lecanemab based on mid-stage trial data showing treatment could eliminate amyloid in the brain. Roche, meanwhile, recently informed trial investigators it would not seek an expedited OK for its drug.

Phase 3 data from both companies aren't expected until the second half of the year, although one of Roche's trials — dubbed Graduate 1 — is earmarked to be completed by May on a federal database of clinical trials. Either way, the studies will be closely tracked throughout the year.

Eli Lilly, meanwhile, could quickly follow Roche and Eisai with Phase 3 data for its Alzheimer's drug donanemab by mid 2023. The pharma has also applied for accelerated approval based on amyloid-reduction data and expects an FDA decision toward the end of 2022.

COMPANY:
 
AbbVie
DISEASE:
 
Cystic fibrosis
TREATMENT TYPE:
 
Small molecule
TRIAL:
 
WHY THEY'RE IMPORTANT:

One by one, Vertex Pharmaceuticals has held off would-be competitors to its four dominant cystic fibrosis drugs, which now generate almost $7 billion each year. But the biotech's stiffest test may be just around the corner.

Early this year, AbbVie is expected to disclose proof-of-concept results for a three-drug combination made of similar components as Trikafta, Vertex's own triplet for CF and its top-selling medicine. The program is part of a long-running effort by AbbVie to challenge Vertex's leadership in CF. The pharma giant worked with Galapagos NV for five years before deciding to acquire the Belgian biotech's cystic fibrosis portfolio in 2018, a move that surprised analysts at the time given the disappointing early results some of the drugs had produced.

But AbbVie has since worked to improve the drug combination, making changes to two of its three components. The company is hoping to see "an efficacy advantage," even a small one, over Trikafta, chief commercial officer Jeff Stewart said on a conference call earlier this year. Though AbbVie isn't expecting full results until the end of 2022, it'll publicly disclose some findings in the first quarter. Separate data from a two-drug regimen are expected as well.

The results have significant implications for Vertex, whose efforts to establish a business outside of cystic fibrosis have underwhelmed.

COMPANY:
 
Gilead
DISEASE:
 
Breast cancer
TREATMENT TYPE:
 
Antibody-drug conjugate
TRIAL:
 
WHY IT'S IMPORTANT:

Gilead has spent more than a decade and billions of dollars trying to become a major player in oncology, with mixed results. The company has won approvals of three cancer drugs in the last four years, but sales are dwarfed by the HIV medicines for which it's long been known.

The cancer drug Trodelvy is meant to help change the narrative for Gilead, and is the key reason the biotech shelled out $21 billion for the medicine's developer, Immunomedics, in 2020.

Currently, Trodelvy is only approved for late-line use in triple-negative breast cancer and a form of bladder cancer. For the drug to become the blockbuster medicine Gilead envisions, Trodelvy has to succeed in an ongoing Phase 3 study known as TROPiCS-02.

The trial is testing Trodelvy against several chemotherapies in patients with HR-positive, HER2-negative breast cancer, a form of the disease accounting for 60% to 70% of all breast cancer cases. Patients in the study have seen their disease progress despite two to four prior treatments, among them a relatively new type of breast cancer drug known as a CDK 4/6 inhibitor.

A positive result in the first quarter of 2022 is crucial for Gilead. Success would open up a $2 billion revenue opportunity for Trodelvy, add 5% to 8% to Gilead's shares and validate the Immunomedics deal, wrote Brian Abrahams, an analyst at RBC Capital Markets.

COMPANY:
 
Karuna Therapeutics
DISEASE:
 
Schizophrenia
TREATMENT TYPE:
 
Small molecule
TRIAL:
 
WHY IT'S IMPORTANT:

Developing new drugs for psychiatric disorders is notoriously difficult, which is why any medicine that shows promise draws close attention. KarXT, a drug developed by Karuna Therapeutics, is a good example. Compelling results in a Phase 2 schizophrenia study added billions of dollars to the company's market value and made it one of the field's most closely watched medicines.

KarXT combines the powerful antipsychotic xanomeline and a chemical, trospium, that's meant to blunt its potentially problematic side effects like sedation and vomiting. Lilly developed and then shelved xanomeline in the 1990s because of those issues. But Karuna's drug showed few signs of them in mid-stage testing while producing a notable effect on schizophrenic symptoms.

That's supported a reevaluation of xanomeline and other drugs like it, which act on nervous system proteins known as muscarinic receptors. A similar medicine from Cerevel Therapeutics has also shown promise. And Karuna has since launched additional studies for KarXT, among them a Phase 2 study in Alzheimer's patients with psychosis.

Analysts at Stifel expect the muscarinic drug class to be worth about $4 billion in schizophrenia. A lot is therefore riding on Karuna's Phase 3 study, called EMERGENT-2 and expected to deliver results by the middle of the year. Many promising neurological drugs have fallen short in late-stage testing before, though, often because of higher-than-expected placebo effects.

COMPANY:
 
Intercept Pharmaceuticals
DISEASE:
 
Non-alcoholic steatohepatitis
TREATMENT TYPE:
 
Small molecule
TRIAL:
 
WHY IT'S IMPORTANT:

Few biotechs have had a more dramatic rise and fall than Intercept Pharmaceuticals, shares of which have swung from more than $400 apiece to less than $16 during the tumultuous saga of obeticholic acid, its drug for a fatty liver disease known as NASH.

Intercept backed up encouraging early clinical results with apparent success in the Phase 3 REGENERATE study in 2019, positioning the company to bring the first treatment to market for NASH, a disease thought to affect millions of people in the U.S. The Food and Drug Administration, however, wasn't convinced the benefits outweighed the potential risks, among them cardiometabolic side effects. The agency asked Intercept for more data from the trial, leading to a lengthy delay, a corporate restructuring and several senior executive departures.

But Intercept still has a chance to rebound. Would-be rivals like Gilead, Genfit and NGM Biopharmaceuticals failed to capitalize on Intercept's stumbles as NASH proved a tougher target than previously expected. Others, such as Madrigal Pharmaceuticals, are still awaiting Phase 3 results.

Intercept, then, could still win the first NASH drug approval if updated results from REGENERATE are positive. The results, which are expected early this year, will include substantially more safety data than were in Intercept's original filing, as well as 18-month liver biopsy analyses from 500 more patients.

Late-stage results are also due from REVERSE, a study that enrolled NASH patients with cirrhosis but who haven't yet shown symptoms. The overall data set should provide "long-awaited clarity on the viability of [obeticholic acid] in NASH," Thomas Smith, an analyst at SVB Leerink, wrote recently.

COMPANY:
 
Allogene Therapeutics
DISEASE:
 
Large B-cell lymphoma
TREATMENT TYPE:
 
Cell therapy
TRIAL:
 
WHY IT'S IMPORTANT:

This past year was challenging for the field of so-called off-the-shelf CAR-T therapy. Meant to be a more convenient alternative to the personalized cell treatments now used to fight several blood cancers, allogeneic treatments, as they're known, haven't yet proven as durable as their more complex counterparts. But the biggest surprise came in October, when the FDA suspended clinical studies run by Allogene Therapeutics, one of the field's leading companies.

The move was made after researchers discovered a "chromosomal abnormality" in one patient treated with ALLO-501a, a lymphoma treatment Allogene had selected for advancement. Though the clinical significance of that finding isn't yet known, the agency responded firmly, halting testing of not just ALLO-501a, but all of Allogene's other programs as well.

Since then, Allogene has been working with the FDA to understand whether the gene editing involved in preparing its treatment is to blame. For its part, the company has downplayed the event, with executives expressing surprise at the FDA's actions.

Even so, the clinical hold nearly halved Allogene's share price and added new questions about off-the-shelf treatments. The results of the investigation and restart of testing, which multiple analysts expect this year, could have far-reaching implications for Allogene and other developers of off-the-shelf cell therapies, many of which involve gene editing.

COMPANIES:
 
GlaxoSmithKline, Pfizer
DISEASE:
 
Respiratory syncytial virus
TREATMENT TYPE:
 
Vaccine
TRIALS:
 
WHY THEY'RE IMPORTANT:

Vaccines for COVID-19 have dominated the world's attention over the past two years, becoming some of the most widely used and lucrative products in the pharmaceutical industry's history. Fewer headlines have covered a high-stakes race to develop shots for another common and potentially deadly infection caused by respiratory syncytial virus. Important clinical trial results are expected this year.

RSV, as it's more commonly known, causes an estimated 177,000 hospitalizations among older adults each year and 58,000 in children under five. The virus has proven a tough target for drugmakers: efforts dating back to the 1960s to develop a vaccine have been unsuccessful. The only way to combat infections is antiviral treatment; synthetic antibodies can also be used to prevent the disease they cause.

That could soon change. GlaxoSmithKline, Pfizer and Johnson & Johnson have each developed shots that train the body to recognize a viral protein RSV uses to infect human cells. All three vaccines are now in late-stage testing, with Pfizer and GSK anticipating initial Phase 3 data by the middle of the year and J&J shortly afterwards.

The financial implications for the studies are significant. Cowen analysts forecast the market for RSV vaccines will be worth nearly $10 billion by 2028.


COMPANY:
 
Alnylam Pharmaceuticals
DISEASE:
 
ATTR cardiomyopathy
TREATMENT TYPE:
 
RNA interference
TRIAL:
 
WHY IT'S IMPORTANT:

One of 2021's more surprising trial failures came during its final week, when a drug for a form of the rare genetic disease transthyretin amyloidosis that affects the heart didn't outperform placebo in a Phase 3 study. The results were "baffling," Neil Kumar, the CEO of the drug's developer, BridgeBio, said in an announcement that sent shares falling by nearly 80%. And they've raised the stakes for an Alnylam Pharmaceuticals study that should deliver data in the middle of 2022.

Alnylam's Onpattro was the first RNA interference medicine to get to market when the FDA approved it in 2018 for the nerve damage associated with transthyretin amyloidosis, or ATTR. Alnylam has since won approvals of multiple other RNAi drugs, but Onpattro remains its top-seller. And one key to its growth is proving Onpattro can help ATTR patients with heart problems — a faster-moving, deadlier and more common form of the condition.

The APOLLO-B study is meant to do just that, and Alnylam has produced encouraging early results from the trial. This year Alnylam will report whether Onpattro can help patients perform better than a placebo on a test of how far they can walk in six minutes after one year of treatment. That's the same measure on which BridgeBio's drug failed, largely because placebo recipients fared significantly better than they have in previous ATTR studies.

BridgeBio says it doesn't yet know why its drug fell short. Nonetheless, Alnylam shares tumbled more than 15% on concerns that the bar for study success in ATTR may now be higher, according to Stifel analyst Paul Matteis. Alnylam, for its part, believes its drug should have a more potent effect because it works differently than BridgeBio's and a similar, approved medicine from Pfizer, Matteis wrote.

https://www.biopharmadive.com/news/biotech-10-clinical-trials-watch-2022-first-half/616458/

5 FDA approval decisions to watch in the first quarter

 The Food and Drug Administration's main drug review office approved 50 new medicines last year, its fourth highest total. Many were for cancer, continuing a trend of recent years, but there were notable new treatments cleared for high cholesterol, HIV and, most controversially, Alzheimer's disease.

The busy pace looks set to continue in 2022, too, as the FDA works with industry to wrap up its latest agreement governing review timelines and user fees. Ahead of the agency this quarter are a number of notable approval decisions, five of which are outlined below.

At face value, approval of yet another so-called checkpoint inhibitor — a type of cancer immunotherapy available for dozens of tumor types — wouldn't seem all that newsworthy. Eight of these drugs are already cleared, seven of which work similarly to Eli Lilly and Innovent Biologics' would-be immunotherapy sintilimab.

But the FDA's review of sintilimab, marketed in China as Tyvyt, is notable nonetheless, because it will show what the agency and its advisers think of an immunotherapy developed and exclusively tested in China.

Lilly acquired rights to Tyvyt from China's Innovent, and now aims to win U.S. approval without having to run a head-to-head study against an established checkpoint inhibitor. (Tyvyt was tested against chemotherapy alone in the trial supporting its application.)

Though not discussing Tyvyt specifically, Richard Pazdur and Julia Beaver, two of the FDA's top cancer drug officials, indicated in a recently published paper that such a study would "probably be required" in such a scenario. They also emphasized that the results of a clinical trial conducted overseas must be generalizable to the U.S. population.

The agency is holding an advisory meeting on Lilly's application on Feb. 10, and the implications are significant for the company and others, like Coherus Biosciences, that are looking to follow a similar path. What's more, Lilly has hinted it may undercut established checkpoint drugs on price, something that hasn't happened despite their widespread availability.

Bristol Myers Squibb's relatlimab in melanoma

Two types of checkpoint inhibitors are approved in the U.S. By mid-March, there could be a third as the Food and Drug Administration is set to decide on an immunotherapy developed by Bristol Myers.

The drug, known as relatlimab, is aimed at a different cellular target than earlier checkpoint inhibitors from Bristol Myers and companies like Merck, Roche and Regeneron. While those treatments work by blocking the proteins known as CTLA-4, PD-1 or PD-L1, relatlimab homes in on one called LAG-3.

The idea is similar, however. By blocking these proteins, immunotherapy helps cancer-fighting immune cells target and attack tumor cells.

An approval would be important for both the immunotherapy field, which has spent years seeking additional ways to unblind the immune system to cancer, and for Bristol Myers, which lost an early market advantage to Merck.

In clinical testing, combining relatlimab with Opdivo significantly reduced the risk of cancer progression over Opdivo alone in people whose melanoma had either spread or couldn't be surgically removed. The results were the first definitive proof that targeting LAG-3 can be beneficial, and the first time a treatment regimen had been shown to improve on Opdivo.

The FDA will make its decision by March 19.

Gilead's lenacapavir in HIV

For years, Gilead has maintained the world's leading business for HIV treatment. The first nine months of 2021 alone saw the company's line of medications for the virus generate about $11.8 billion in sales.

And yet, Gilead remains under constant pressure to innovate thanks to competition from deep-pocketed and powerful rivals like Merck, Johnson & Johnson and GlaxoSmithKline. On that front, a drug called lenacapavir has become important to Gilead's future.

Lenacapavir is designed to attach to the capsid — the shell that encases the virus' genetic information — and stop it from breaking apart, thereby impeding the HIV replication process.

Gilead has already scored positive clinical trial results showing that its drug helped suppress HIV in patients who had tried multiple other therapies but were no longer responding to them. Among the few dozen patients who've been evaluated thus far, around 80% had viral loads so low they were undetectable six months after starting treatment with lenacapavir and an optimized background regimen.

Based on those results, Gilead formally asked the FDA to approve lenacapavir last summer. A decision from the agency is expected by Feb. 28. If approved, it would be the first capsid inhibitor ever cleared for market, and the only HIV treatment option that's given every six months. (The review doesn't involve a different, injectable version of Gilead's drug, for which testing was recently halted.)

Analysts expect a title like that should translate to blockbuster sales over time. In fact, lenacapavir could deliver north of $1.1 billion to Gilead by 2030, according to consensus estimates compiled by the investment bank Mizuho Securities.

Akebia's vadadustat for anemia in chronic kidney disease

Not long ago, a group of pills known as HIF-PH inhibitors were supposed to be the next big thing in anemia care for people with failing kidneys. But their potential as convenient and safer alternatives to injectable drugs like Aranesp has dimmed.

A drug from Akebia Therapeutics called vadadustat, for example, appeared worse than Aranesp on a measure of heart safety in a Phase 3 trial the biotech reported in 2020. The FDA and its advisers then rejected FibroGen's roxadustat — already approved in several other countries — after its advisers flagged concerns about cardiovascular risk. FibroGen has since restructured, while shares of Akebia are trading at all-time lows.

HIF-PH blockers could still have a future in the U.S., however. In November, GlaxoSmithKline detailed positive Phase 3 results for its drug daprodustat, which is also approved overseas. And Akebia, despite its setbacks, has moved forward with an approval application, arguing the totality of its study results are good enough to secure regulatory clearance.

That belief will be put to the test this quarter. Though analysts have been skeptical the drug can win clearances for the broadest group of chronic kidney disease patients, some believe the FDA will approve it for those on dialysis, which still represents a sizable market.

The agency will make a decision by March 29.

AstraZeneca and Merck's Lynparza for early breast cancer

Lynparza, a type of cancer medicine known as a PARP inhibitor, has led the way for its class, winning approvals in multiple tumor types and becoming a multibillion dollar drug in the process. But its biggest impact yet could come soon, if the FDA approves it for early use in a particularly aggressive, hereditary form of breast cancer.

In a Phase 3 trial last year, Lynparza helped slow the return of HER2-negative tumors in women with an inherited mutation to the genes BRCA1 or BRCA2, which account for about 5% of all breast cancer cases. That benefit was observed when Lynparza was administered as an "adjuvant" treatment after surgery to remove a tumor and other standard drugs like chemotherapy. Treatment helped patients with both local as well as distant tumors, the latter of which can be particularly lethal.

Experts uninvolved with the study and interviewed by BioPharma Dive described the results as potentially practice-changing. But key questions remain, most notably how long Lynparza can extend lives and whether the drug's emergence will encourage BRCA testing. If cleared, Lynparza would also become the latest high-priced cancer medicine to move into an earlier setting, which are viewed as lucrative opportunities for drugmakers.

https://www.biopharmadive.com/news/5-fda-approval-decisions-first-quarter-2022/616660/

As 3 biotechs head to Wall Street, battered sector braces for pullback

 Three drug developers have raised roughly $480 million combined in the biotech sector's first initial public stock offerings of 2022. Their performance, as well as that of the companies that join them in the weeks and months ahead, will be an important barometer for an industry that ended a record-setting year on a sour note.

The three biotechs making their debuts on the Nasdaq stock exchange Friday are Amylyx PharmaceuticalsCinCor Pharma and Vigil Neuroscience. Of the three, only Vigil priced shares below its projected ranges, while CinCor and Amylyx each sold more shares than they originally planned.

The offerings are a positive, though preliminary, sign there is still demand among investors to participate in the IPOs of emerging biotechs despite a up-and-down 2021. Yet industry analysts nonetheless expect a significant pullback for initial stock offerings, which are often viewed as a bellwether for the biotech industry, fueling the clinical development plans of young drugmakers and generating returns for the venture investors who back them.

New IPOs "will get done," wrote analysts at SVB Leerink in a recent report, but "volume, size, and value [are] likely to be materially reduced."

Biotech IPOs peaked and then crashed in 2021, the culmination of a boom that began early last decade and soared to record heights during the coronavirus pandemic. According to data compiled by BioPharma Dive, 78 drug developers raised at least $50 million in an IPO in 2021, outstripping a record total set just a year earlier. Those offerings collectively pulled in nearly $14 billion — slightly below the roughly $15 billion that offerings amassed a year earlier, but far outpacing the $4.7 and $5.4 billion respectively raised in 2019 and 2018.

Yet nearly 80% of the class finished the year trading below their offering prices, a sharp contrast to prior years' performance and a warning sign for the sector. The 30-day return for the class was about 1%, versus 30% a year before, according to SVB Leerink.

A Jan. 2 report from investment bank Jefferies, meanwhile, found the average biotech IPO was down 22% in 2021, compared to gains of anywhere from 10% to 100% between 2016 and 2020. The lackluster results were the worst for an IPO class since 2016, Jefferies analysts wrote, and mirrored biotech index funds, which significantly underperformed compared to the broader market.

The amount raised in IPOs tracked by BioPharma Dive also fell in 2021, declining from an average offering of $207 million in 2020 to an average of $174 million last year.

Over the course of the year, some industry watchers viewed the lagging performance as a reversion to pre-pandemic norms for biotech stocks. Others noted that the private investors backing them were often still "well in the money," an indication of the strength of the IPO market compared to past years.

Shares in publicly traded companies soared to record levels in 2020, lifted by the successful development of coronavirus vaccines and drugs, and new IPOs were carried along with them. That led to private companies raising the funding rounds that precede IPOs at higher and higher valuations, which became tougher for biotechs to carry into an offering and sustain afterwards.

Those high valuations were increasingly held by biotechs going public earlier and earlier, often before any proof in clinical testing that their drugs hold promise. In 2021, for example, 52 of the 78 biotech IPOs tracked by BioPharma Dive were in preclinical or Phase 1 testing, up from 47 in 2020. Both numbers were more than double what was seen in 2019 and 2018. The stock prices of several of those companies collapsed following early clinical setbacks.

As a result, Jefferies' analysts wrote, investors are "fatigued" by the high values of companies "trying to outdo each other to get the highest valuation when they go out." The continuous step-ups left public investors who bought into IPOs holding stocks at higher valuations, despite the fact those biotechs hadn't hit any new milestones to support them, the analysts added. (Notably, Amylyx and CinCor, which both raised much larger sums than the preclinical biotech Vigil, have drugs in either mid- or late-stage testing.)

"We'd like to see a healthy pace of transactions at less step up, more conservative valuations, and a realization that when IPOs do well, the whole sector can do better and it makes investors less turned off," Jefferies analysts wrote. "Valuations should go up when companies hit milestones and show good data but instead companies were having to 'grow into' their valuations."

As a result, they and others expect fewer IPOs, as well as other types of financing rounds, in 2022. Analysts at investment firm Baird, for example, predict a "moderation" in both the numbers and amounts raised in financings. "Capital has been almost limitless in the last few years, but there are multiple signs of that drying up," they wrote, adding that they wouldn't be surprised to see "some down rounds," or financings at lower valuations, coming.

"Although we don't expect a complete closure of the window," Baird analysts wrote, "we believe we could see a significant falloff."

https://www.biopharmadive.com/news/biotech-ipo-performance-investors-2021/616808/

Decreasing cancer drugs’ side effects

 Millions of people around the globe are affected by cancer each year; more than 39% of men and women are diagnosed with cancer during their lifetime. Chemotherapy is the most commonly employed, standard cancer treatment and targeted delivery of these drugs to the tumor site increases their effectiveness. However, excess drugs may still circulate to the rest of the body and cause multiple side effects, including anemia, chronic infections, hair loss, jaundice and fever.

 

A number of proposed methods have been attempted to remove unwanted chemotherapeutic drugs, particularly the widely used drug doxorubicin (DOX), from the blood. But these methods have resulted in insufficiently low levels of DOX removal. Additional strategies which use electrically charged nanoparticles for binding DOX lose effectiveness with exposure to the charged molecules and proteins found in blood, despite the addition of materials intended to protect binding capacity.

 

A collaborative team, which included scientists from The Pennsylvania State University and the Terasaki Institute for Biomedical Innovation (TIBI), has devised a method to address these challenges.

 

The method, described in Materials Today Chemistry, is based on hairy cellulose nanocrystals — nanoparticles developed from the main component of plant cell walls and engineered to have immense numbers of polymer chain “hairs” extending from each end. These hairs increase the potential drug capture capacity of the nanocrystals significantly beyond that of conventional nanoparticles and other materials.

 

To produce the hairy cellulose nanocrystals capable of capturing chemotherapy drugs, the researchers chemically treated cellulose fibers found in softwood pulp and imparted a negative charge on the hairs, making them stable against the charged molecules found in blood. This corrects the problems found with conventional nanoparticles, whose charge can be rendered inert or reduced when exposed to blood, limiting the number of positively charged drug molecules it can bind to in insignificant numbers.

 

The nanocrystals’ binding efficacy was tested in human serum, the protein-rich liquid portion of blood. For every gram of hairy cellulose nanocrystals, more than 6,000 milligrams of DOX were effectively removed from the serum. This represents an increase in DOX capture of two to three orders of magnitude compared to other methods currently available.

 

Furthermore, DOX capture occurred immediately after addition of the nanocrystals and the nanocrystals had no toxic or harmful effects on red blood cells in whole blood or on cell growth of human umbilical cells.

 

Such a powerful means of drug capture within the body can have a great impact on cancer treatment regimens, as doses can be elevated to more effective levels without the worry of detrimental side effects.

 

Principal investigator, Amir Sheikhi, assistant professor of chemical engineering and biomedical engineering at Penn State, offered an example of such an application. “For some organs, like the liver, chemotherapy can be locally administered through catheters. If we could place a device based on the nanocrystals to capture the excess drugs exiting the liver’s inferior vena cava, a major blood vessel, clinicians could potentially administer higher doses of chemotherapy to kill the cancer more quickly without worry about damaging healthy cells. Once the treatment is finished, the device could be removed.”

 

In addition to removing excess chemotherapeutic drugs from the body, the hairy cellulose nanocrystals could also target other undesirable substances such as toxins and addictive drugs for removal from the body, and experiments have also demonstrated the nanocrystals’ effectiveness in other separation applications, such as in the retrieval of valuable elements from electronic waste.

 

“What began as a relatively simple concept has evolved into a highly effective means of materials separation,” said Ali Khademhosseini, Director and CEO at the Terasaki Institute for Biomedical Innovation. “This creates the potential for wide-ranging and impactful biomedical and materials science applications.”

 

Additional authors are Sarah A.E. Young, Joy Muthami, Mica Pitcher, Petar Antovski, Patricia Wamea, Robert Denis Murphy, Reihaneh Haghniaz, Andrew Schmidt, and Samuel Clark.

 

This work was supported by the National Institutes of Health (1R01EB024403-01).

PRESS CONTACT

 

Stewart Han, shan@terasaki.org, +1 818-836-4393

Terasaki Institute for Biomedical Innovation

 

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The Terasaki Institute for Biomedical Innovation (terasaki.org) is a non-profit research organization that invents and fosters practical solutions that restore or enhance the health of individuals.  Research at the Terasaki Institute leverages scientific advancements that enable an understanding of what makes each person unique, from the macroscale of human tissues down to the microscale of genes, to create technological solutions for some of the most pressing medical problems of our time.  We use innovative technology platforms to study human disease on the level of individual patients by incorporating advanced computational and tissue-engineering methods.  Findings yielded by these studies are translated by our research teams into tailored diagnostic and therapeutic approaches encompassing personalized materials, cells and implants with unique potential and broad applicability to a variety of diseases, disorders and injuries. 

The Institute is made possible through an endowment from the late Dr. Paul I Terasaki, a pioneer in the field of organ transplant technology.

Simple pH adjustment may enable preventative Covid-19 nasal and throat spray

 Mechanical engineering and materials science professor David Needham has shown that a slight increase in solution pH might be all it takes to turn a metabolic inhibiting drug, traditionally used to treat gut parasites, into a promising prophylactic/preventative nasal spray and early treatment throat spray for COVID-19.

The results appear online on December 28 in the journal Pharmaceutical Research.

Since 1958, niclosamide has been used to treat gut parasite infections in humans, pets and farm animals. Delivered as oral tablets, the drug kills the parasites on contact by inhibiting their crucial metabolic pathway and shutting down their energy supply.

In recent years, however, researchers have been testing niclosamide’s potential to treat a much wider range of diseases, such as many types of cancer, metabolic diseases, rheumatoid arthritis and systemic sclerosis. Recent laboratory studies in cells have also shown the drug to be a potent antiviral medication, inhibiting a virus’s ability to cause disease by targeting the energy supply of the host cell that the virus co-opts for its self-replication.

Niclosamide primarily acts upon host cell’s mitochondria, which are like energy-producing batteries of the cell. The drug prevents the cell from producing its main energy molecule, adenosine 5'-triphosphate, or ATP. Without the infected cell’s energy supply, the virus has trouble replicating viable copies of itself to cause further infections. These effects are reversible and do not result in any cell death.

“Niclosamide turns down the dimmer switch on a cell’s energy and essentially puts the virus in lockdown,” said Needham, the sole author of the new study. When used in conjunction with vaccines, masking and other recommended mitigation measures for COVID prevention, the new niclosamide solution holds potential as an adjunct strategy, he said. “This development could enable safe and effective nose and throat sprays that provide additional protection behind the mask.”

Pivoting During a Pandemic

In an ongoing collaboration with Will Eward, a surgical oncologist at Duke, Needham had already shown that niclosamide has activity in bone cancer in mice and dogs when made into a nanoparticle that essentially, as he says, “makes the drug look like the cancer’s food.” In another collaboration with Christina Barkauskas, assistant professor of medicine in Pulmonary Medicine at Duke,  they were starting preliminary studies on potentially using the same niclosamide formulation for lung fibrosis when the pandemic hit. 

Like many researchers worldwide, Needham switched gears to COVID-directed studies. After a Korean paper screening existing drugs for efficacy against COVID-19 identified niclosamide as a potential target, he spent the next year researching a range of solution, nanoparticle and microparticle formulations. The Korean studies in animal cells showed that it only took a low concentration of niclosamide before infection to completely stop the SARS-COV-2 virus from replicating.

The animal cells being used, however, are extremely hardy and durable. To find out how effective and tolerable niclosamide might be for human use to fight COVID-19, Needham and Barkauskas turned to cells that were more pertinent to the initial nasal and bronchial infection—respiratory epithelial cells—and engaged other clinical researchers at Duke.

Without live virus to test with, the researchers focused on measuring how much niclosamide reduces human airway cells’ levels of ATP. Based on the Korean study’s ATP-to-viral-inhibition measurements, Patty Lee, professor of medicine, cell biology and pathology at Duke, and her postdoc Sojin Kim, found that just a few micromolar concentration of the drug can lower ATP levels enough to potentially cut virus reproduction completely without harming the cells themselves.

These studies were, however, conducted on cells submerged in cell culture media, which slows the rate at which niclosamide is absorbed and can act in the cells. In further benchtop cell studies with Barkauskas and Zach Kelleher, a laboratory technician in her lab, the researchers focused on human airway cells treated with just the buffered niclosamide solution. Funded by a grant from the American Lung Association, the study suggests that even lower doses are enough to positively affect airway cells.

But all three of these studies don’t take the mucus into account.

The Need for Reformulation

Traditional allergy medicines such as Flonase and Nasonex carry roughly 6,000 to 30,000 times more of their respective active ingredients in solution than would be needed to affect cells in benchtop studies. This is because only a small amount of the active drug actually makes it past the protective layer of mucus constantly covering the backs of peoples’ noses and throats.

Niclosamide, however, is not easily dissolved into water-based liquids that can be sprayed into a person’s nose and mouth. The drug’s normal attainable solution concentration at a nasal pH of around 6 or 7 is close to, or even less than, what the benchtop studies suggest is required to stop the virus from replicating in cells without protective mucus.

Based on calculations of how molecules like niclosamide diffuse through a thin layer of mucus, Needham estimates that a solution concentration that is about 10 times greater than that typically attainable is needed to produce a functioning prophylactic and treatment spray, and that it can get through the mucus layer in a matter of milliseconds.

The question for Needham was, then, how to get to that concentration.

Adjusting the pH

In the new paper, Needham demonstrates that simply raising the alkalinity of the solution might be enough to get through the mucous barrier and into the cells where a COVID-19 infection first takes hold. He found that raising the solution’s pH to a slightly alkaline pH of 8.0—acceptable for a nasal spray—can dissolve enough niclosamide to meet the requirement of his calculations. And raising the pH to 9.2, which is still tolerable for a throat spray, beats that benchmark by 10 times more and could be used in early infection.

While promising, Needham notes, these results still need to be tested in cells actually infected with COVID-19, as well as in such cells protected by a mucus layer, which requires finding partner labs and agencies with the required biocontainment resources and live virus.

A protocol to make liter-sized batches that can be filled and sealed in sterile-capped, 10mL vials has already been developed in the Duke compounding pharmacy by Vincent Gaver, clinical research pharmacist, and Beth McLendon-Arvik, director of Investigational Drug Services. And in his new patent application, Needham also described a method for extracting niclosamide from commercially available tablets into the solution without using organic solvents.

“Because it works on the cells rather than the virus, niclosamide could function as a respiratory viral prophylactic agent, not just against COVID-19 and all of its variants, but against any new virus as well,” Needham said. “While vaccines are clearly effective, a nasal preventative would added protection. And even if an infection has already taken hold, this formulation could be used as an early treatment throat spray that could stop the viral load heading toward the lungs that causes the disease’s most devastating effects.”

Needham has already filed a patent application and is actively seeking industry, government and infectious disease institute partners to help pursue clinical trials and commercialization.

CITATION: “The pH Dependence of Niclosamide Solubility, Dissolution, and Morphology: Motivation for Potentially Universal Mucin-Penetrating Nasal and Throat Sprays for COVID19, its Variants and other Viral Infections,” David Needham. Pharm Res, 2021. DOI: 10.1007/s11095-021-03112-x

Patent Application: “NICLOSAMIDE NASAL AND THROAT SPRAY” Inventor, David Needham, PCT/US21/72303

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Blood test helps predict who may benefit from lung cancer screening

 A blood test, combined with a risk model based on an individual’s history, more accurately determines who is likely to benefit from lung cancer screening than the current U.S. recommendation, according to a study published today in the Journal of Clinical Oncology led by researchers from The University of Texas MD Anderson Cancer Center.

A personalized lung cancer risk assessment, combining a blood test based on a four-marker protein panel developed at MD Anderson and an independent model (PLCOm2012) that accounts for smoking history, was more sensitive and specific than the 2021 and 2013 U.S. Preventive Services Task Force (USPSTF) criteria. The study included participants from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial with at least a 10 pack-year smoking history. If implemented, the blood test plus model would have identified 9.2% more lung cancer cases for screening and reduced referral to screening among non-cases by 13.7% compared to the 2021 USPSTF criteria.

“We recognize that a small percentage of people who are eligible for lung cancer screening through an annual low-dose CT scan are actually getting screening. Moreover, CT screening is not readily available in most countries. So, our goal, for many years, has been to develop a simple blood test that can be used first to determine need for screening and make screening for lung cancer that much more effective,” said Sam Hanash, M.D., Ph.D., professor of Clinical Cancer Prevention and leader of the McCombs Institute for the Early Detection and Treatment of Cancer. “Our study shows for the first time that a blood test could be useful to determine who may benefit from lung cancer screening.”

The USPSTF recommends that adults at high risk for lung cancer receive a low-dose CT scan each year, which was shown to reduce lung cancer deaths in the 2011 National Lung Screening Trial (NLST). The 2021 USPSTF criteria applies to adults age 50 to 80 who have at least a 20 pack-year smoking history and currently smoke or have quit within the past 15 years.

Hanash and colleagues developed a blood test incorporating biomarkers that they previously identified as predictive of lung cancer risk. A multicenter team used a blinded study to evaluate the performance of this four-protein marker panel in combination with the PLCOm2012 model, which was independently developed and validated to predict a six-year risk for lung cancer among individuals who currently smoke or smoked formerly.

“When we began work on a blood test, there were many different types of markers,” Hanash said. “We’ve done multiple analyses over the past decade to come up with a cost-effective test that’s simple, yet robust, which has been the guiding principle of our research.”  

To test the combination of blood markers with the PLCOm2012 model, the researchers analyzed more than 10,000 biospecimens from the PLCO study, including 1,299 blood samples collected from 552 individuals who developed lung cancer and 8,709 samples collected from 2,193 people who did not develop lung cancer. 

Among individuals with at least a 10 pack-year smoking history, the combined blood test with PLCOm2012 model showed overall improved sensitivity (88.4% versus 78.5%) and improved specificity (56.2% versus 49.3%), compared to the current USPSTF criteria. If implemented, the combined personalized risk assessment would have identified 105 of the 119 people in the PLCO intervention arm who received a lung cancer diagnosis within one year. 

“A blood test would identify people who could benefit from lung cancer screening but are not eligible today,” Hanash said. “Tens of millions of people worldwide could benefit from lung cancer screening. If you can improve screening eligibility by even 5%, that is incredibly impactful.”

While the blood test could be implemented as a lab-developed test in the near future, Food and Drug Administration approval likely would require evaluation through a prospective clinical trial.

The study was supported by the National Institutes of Health and National Cancer Institute (U01CA194733, U01CA213285, U24CA086368, U01 CA200468), the Cancer Prevention & Research Institute of Texas and Lyda Hill Philanthropies. Additional research support was provided by the Lung Cancer Moon Shot®, part of MD Anderson’s Moon Shots Program®, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.

Hanash is an inventor on a patent application related to the blood test. A complete list of co-authors, their affiliations and their disclosures is included in the paper.