Bristol Bails on Checkpoint Inhibitor Teaming with CytomX

 Bristol Myers Squibb is leaving CytomX scratching its head with the “unexpected decision” to discontinue its partnered program for a more potent version of the BMS immunotherapy Yervoy. CytomX announced the update with its 2023 financial results late Monday, sending its stock tumbling around 20% in premarket trading Tuesday. 

In an earnings call, CytomX CEO Sean McCarthy said BMS informed the company of its decision to terminate on March 6, following a broad internal portfolio review. The biotech intends to work with BMS to understand the data that led to the decision, according to McCarthy.  

BMS had prioritized the program, dubbed BMS-986288, as its lead next-gen CTLA-4 program and advanced it into Phase II studies last year. Utilizing CytomX’s Probody therapeutic technology, it is designed to be a more potent and less systemically toxic version of Yervoy, BMS’s CTLA-4-blocking antibody.  

Yervoy is currently approved for seven types of cancers including melanoma and colorectal cancer. The drug is one of BMS’ top cancer drugs, raking in over $2.2 billion in sales in 2023.This isn’t the first time a BMS decision has sent CytomX stock tumbling. In 2019, BMS reprioritized the pipeline after its Celgene acquisition and terminated three discovery programs with CytomX. That decision sent the biotech’s stock into a 30% nosedive. BMS paid $50 million to strike up the initial collaboration with CytomX nearly 10 years ago, paying $50 million at the time. 

However, the two will continue to work together in other collaborations involving T-cell engagers, which is the focus of most of CytomX’s partnered programs. The biotech also has deals with Amgen, Astellas, Moderna and Regeneron. 

CytomX is still eligible to receive $1.8 billion in contingent payments for development, regulatory and sales milestones for the ongoing collaboration programs with BMS, according to its SEC filing. 

https://www.biospace.com/article/bms-bails-on-checkpoint-inhibitor-teaming-with-cytomx-stock-sinks-/

A Year After Silicon Valley Bank’s Collapse, Biotech Looks Back on the Crisis

 In mid-March 2023, Paul Hastings, CEO of cell therapy biotech Nkarta, was seeing news reports of Silicon Valley Bank’s initial troubles and thought it was “weird.” Then it got serious.

Hastings soon received a phone call from Nadir Mahmood, the company’s head of finance at the time. Mahmood said he was not sure how they were going to make payroll on Monday, Hastings recalled in an interview with BioSpace. Hastings said the company was then in the process of transferring money to a different bank, and in the end, the situation was ironed out, “but it was very disruptive for the rest of us for a short period of time.”

That initial shock gave rise to funding concerns, Hastings added. “Silicon Valley Bank was the cornerstone of a lot of our banking activities in our industry—not just biotech, but also tech in Silicon Valley—so it was a little bit hard to accept and swallow that somebody had made the mistakes they had made,” Hastings said. “But they did, and they paid the consequence for it.”

According to a Reuters report from a year ago, 50% of early-stage biotechs banked with SVB. Today, experts told BioSpace, biotech companies have learned from the shocking event to diversify their funds and protect against the downfall of any single institution.

What Caused Silicon Valley Bank to Collapse?

On March 8, 2023, SVB announced in a mid-quarter update that it was undertaking an underwritten public offering to raise around $2.25 billion. But with a perfect storm of rising interest rates, which reduced the value of long-term bonds the bank held,  and a reduction of venture capital deposits, it was facing losses. Once SVB announced that it had sold securities at a loss, panic ensued, leading companies that banked with SVB to withdraw their accounts. This snowballed into a run on the bank.

“Silicon Valley Bank bought a bunch of bonds,” said Steve Wasserman, a consulting part-time CFO and senior lecturer at Bentley University. “When interest rates went up, they ended up losing money.”

SVB had been a significant player in the Bay Area entrepreneurial environment, especially in biotech and the general technology sectors. “[SVB] was very concentrated in a few segments: life sciences and technology,” Wasserman said. “They weren’t very well diversified.”

This did not bode well for SVB when things started to falter, explained George Morgan, a professor of finance at Virginia Tech. “The community that they were serving was pretty tight-knit,” he said. “When a couple of people started to get suspicious about the health of the portfolio, they spread that suspicion around pretty quickly to other community members, and that's sort of what . . . triggered the run.”

Graig Suvannavejh, managing director of equity research at Mizuho Securities, told BioSpace that when the SVB news was breaking, the question was which biotech companies would keep their money in the bank and which would not. “At least that was the initial fear, in the moment, call it a fog of war,” Suvannavejh said.

But as quickly as the chaos came, things began to settle down. Analysts told CNN that the collapse of one prominent bank would not have a cascading effect on the broader U.S. economy. Suvannavejh’s own analyst reports from last year noted that the companies he analyzed were minimally affected, and most companies that had banked with SVB had minimal to no exposure.

Picking Up the Pieces

For investment banks that work in the life sciences industry, SVB’s loss was their gain. First Citizens Bank swiftly acquired SVB, while large banking institutions such as HSBC and JP Morgan Chase bought some of SVB’s assets.

Katherine Andersen, a former SVB executive and now the head of life science and healthcare at HSBC USA commercial banking, noted that HSBC had a “strong desire” to lean into the innovation industry and build off of the assets acquired from SVB. The bank acquired SVB’s U.K. branch in March 2023, giving it a solid foundation, Andersen said, and late last year, HSBC launched a debt program and closed more than 35 deals in the life sciences and healthcare. “We’ve been far more successful than I think I had anticipated,” Andersen said.

Wasserman said that while other banks may have won in this situation, he doesn’t think there were any overall winners in the crisis. Hastings reiterated this sentiment. “Anytime something like that happens, everybody loses,” he said.

To guard against future similar incidents, Hastings said that Nkarta and its peers have improved their own cash management. “They’ve adapted to this new environment, and they’re—if they had put all their eggs in one basket in the past—probably not doing that anymore,” he said. Wasserman, Morgan and Suvannavejh all agreed that having money in different banks would dilute the risk.

The biotech sector is now seeing its financial climate rebound, with more companies going public and with mergers and acquisitions also picking up steam. This should shield investment banks from the risk of the run that put SVB in the ground, Hastings said.

“At the time, we were in a very tough financing environment . . . and we all needed to spend our cash on our pipelines,” he explained. “Now the environment is financings are back, and so the fund flow through the banks [is] more natural now than [it was] back then.”

https://www.biospace.com/article/a-year-after-silicon-valley-bank-s-collapse-biotech-looks-back-on-the-crisis/

Unique Trial Design Expected to be Focus of Upcoming Donanemab Adcomm

 It has been a long road for Eli Lilly’s donanemab—and last Friday, that road got a little bit longer. Lilly had expected a decision from the FDA on its investigational Alzheimer’s drug by the end of 2023. Then, by the end of this quarter. But now, the regulator wants to discuss the drug’s safety and efficacy at a yet–to–be–scheduled advisory committee meeting, leaving open the question of when a final verdict may be rendered.

When a date is set, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee will be looking to glean further insight into donanemab’s safety profile and the potential efficacy implications of Lilly’s “unique” Phase III trial design, according to the company.

Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation, told BioSpace that the FDA’s decision to convene an advisory committee is not wholly unexpected, but the timing of it is. “What was a little surprising is that they’re doing it kind of late in the due diligence process,” he said, speculating that this development could push a decision on donanemab into the summer.

“I actually think it’s a positive thing overall,” Alvaro Pascual-Leone, professor in neurology at Harvard Medical School and medical director at the Wolk Center for Memory Health, Hebrew SeniorLife, said of the upcoming adcomm. “I think that it is a good thing . . .  that the FDA takes these things seriously. I don’t think it means in any shape or form that there are concerns about this medication.”  

In response to BioSpace’s request for comment, an FDA representative said it is the agency’s policy not to discuss pending applications outside the formal advisory committee setting.

The Safety Conversation

In terms of safety, Fillit said the FDA wants to determine whether donanemab’s safety profile is similar to that of Biogen and Eisai’s anti-amyloid antibodies Leqembi and Aduhelm “or if there’s a real problem.”

The biggest strike against this class of Alzheimer’s therapies is the risk of amyloid-related imaging abnormalities (ARIA), or brain swelling. In donanemab’s Phase III TRAILBLAZER-ALZ 2 trial, the incidence of symptomatic ARIA-E was 6.1% with donanemab versus 0.1% in the placebo arm. In Leqembi’s Phase III Clarity AD trial, 2.8% of patients who received Leqembi had symptomatic ARIA-E, while none on the placebo did. However, the trials consisted of different patient populations, so the comparison is not apples to apples.

In another study presented at last week’s AD/PD 2024 conference comparing donanemab and Aduhelm, the incidence of ARIA was lower in patients treated with Lilly’s drug. Occurrence of ARIA (both E and H) was 29% for patients treated with donanemab and 40.6% for those treated with Aduhelm. The rate of symptomatic ARIA-E was also lower in donanemab-treated patients at 2.8% versus 7.2% for people taking Aduhelm.

Fillit said he does not see much difference in the safety profiles of these drugs.

Novel Trial Design

Eli Lilly’s trial design consists of two novel aspects. First, the company enrolled patients based partly on levels of tau in the brain; second, patients were allowed to stop treatment once amyloid was determined to be successfully removed. This feature may have tripped up the company’s bid for accelerated approval of the drug, as fewer than 100 patients were on donanemab for 12 continuous months in Lilly’s Phase II trial, a factor the FDA cited in its Complete Response Letter in January 2023.

The Phase III TRAILBLAZER-ALZ 2 enrolled participants with early symptomatic disease based on cognitive assessments along with amyloid plaque imaging and a relatively new measure called tau staging.

Tau staging had not been used in any previous Alzheimer’s trials, Fillit noted. “I think [FDA] wanted to know whether this kind of technology should be included in the label,” he said. This would have implications for payors and patients, he said, “because tau imaging costs money.”

Fillit said donanemab’s limited dosing regimen is very important. “It demonstrates that patients can be monitored and that efficacy can be demonstrated in terms of removal of amyloid from the brain.” This regimen can potentially reduce side effects and lessen the burden on the patient, he said. At the adcomm, Fillit would like to see a discussion around the role of follow up PET scans to determine if amyloid has indeed been removed.

These two aspects of the trial’s design enable a “really individualized, personalized intervention,” Pascual-Leone said. However, as many patients reached the predefined stopping threshold early, this led to a shorter duration of follow-up, which may have limited insights on longer-term safety and duration of benefits. “It is not the traditional way of assessing efficacy and it does mean that the FDA needs to look at it in different ways,” he said.

In an email to BioSpace, Dawn Brooks, global development leader of donanemab at Eli Lilly, expressed confidence in the design. “The efficacy benefit among those who stopped their treatment at either 6 or 12 months continued to separate from placebo over the course of the trial, suggesting that once amyloid is considered cleared that the efficacy benefit continues,” she said.

Pascual-Leone said he would like to learn how to translate the clinical trial data into individual recommendations for patients. “Does this mean we need to determine amyloid status and tau level? Does it mean that therefore a spinal tap is going to be necessary . . . or would two PET [scans] be needed? It is not straightforward; it is challenging, and it is important to discuss.”

Brooks noted that Eli Lilly included tau assessment as a clinical trial design feature to better inform the stage of disease. Based on the results of TRAILBLAZER-ALZ 2, she said, “[w]e have every reason to believe that people with no or very low tau at baseline may see even better outcomes.”

“It’s exciting times,” Pascual-Leone said, “but I think we need to make sure that we don’t miss the learning opportunity.”

https://www.biospace.com/article/unique-trial-design-expected-to-be-focus-of-upcoming-donanemab-adcomm/

Merck Bets Potential $1B on Pearl Bio’s Genomically Recoded Organisms

 Pearl Bio on Tuesday unveiled an alliance with Merck that could see the pharma giant pay up to $1 billion to collaborate on engineered biologics.

Massachusetts-based Pearl Bio is built on the work of Farren Isaacs and Michael Jewett. In 2013, Isaacs, a professor at Yale School of Medicine, published a paper on genomically recoded organisms (GROs) with collaborators including George Church. The big idea is to create proteins from amino acids other than the 20 that exist in nature, thereby unlocking opportunities to create better drug molecules.

Merck sees potential in the idea. Under the terms of the deal, Merck will pay up to $1 billion in option and milestone payments in addition to potential royalties to work with Pearl Bio on GROs and advance drug candidates that emerge from the collaboration.

The partners will initially apply the technology to the discovery and development of anti-cancer biologic therapies. Specifically, the goal is to create “multi-functionalized therapeutic candidates with tunable properties solving for some of the key shortcomings confronting biologics,” Amy Cayne Schwartz, co-founder and president of Pearl Bio, said in a statement.

In theory, the ability to use synthetic amino acids—rather than just the 20 found in nature—could enable researchers to create proteins with enhanced activity and find solutions to long-standing problems, such as how to optimize the drug-antibody ratio in antibody-drug conjugates (ADCs).

Pearl Bio’s team is part of a long line of research groups to explore the use of non-standard amino acids. A paper published in 1993 described the replacement of a natural amino acid with an amino acid analog. Later, other researchers described a different approach that enabled the addition of around 70 unnatural amino acids to the genetic codes of bacteria, yeast and mammalian cells.

Biotechs are active in the space as well. Amrbx, which Johnson & Johnson bought for around $2 billion, is using synthetic amino acids in ADCs. Sanofi bought a synthetic genome company, Synthorx, for $2.5 billion in 2019, only to drop a key program in 2022. GRO Biosciences, as the name suggests, has a GRO platform. Leaps by Bayer and Redmile Group led a $25 million investment in GRO in 2021.

Pearl Bio officially became part of the pack of synthetic biology biotechs when it exited stealth mode last year. As part of its unveiling, the biotech revealed investment from Khosla Ventures and a patent related  to encoding synthetic chemistries to engineer programmable biologics.

https://www.biospace.com/article/merck-bets-up-to-1b-on-pearl-bio-s-genomically-recoded-organisms/

Roche Plots Neuro Comeback with Promising Mid-Stage Alzheimer’s Data

 Roche in a virtual investor event on Monday unveiled promising Phase Ib/IIa data for an investigational Alzheimer’s therapy that could define the pharma group’s neurology franchise in the coming years.

The event spotlighted mid-stage results for trontinemab, an investigational monoclonal antibody targeting amyloid-beta being assessed in Alzheimer’s. Data were presented by Azad Bonni, senior vice president and global head of neuroscience and rare diseases at Roche, which “demonstrated rapid and robust amyloid plaque reduction.”

Developed using Roche’s proprietary Brainshuttle platform, trontinemab can cross the blood-brain barrier and achieve higher levels of brain exposure and broader distribution across the central nervous system, according to the company. The antibody was assessed in a Phase Ib/IIa dose-escalation trial with a staggered, parallel-group and adaptive study design, with four sequential cohorts receiving increasing doses of trontinemab or placebo.

At 28 weeks, patients who received the lowest 0.2-mg/kg dose of trontinemab saw a mean amyloid reduction of 20 centiloid units, compared to only five centiloid units in the placebo group. The second-highest dose of 1.8-mg/kg elicited a mean amyloid drop of 84 centiloid units.

The highest dose of trontinemab—3.6-mg/kg—did not have 28-week data available for analysis, but at 12 weeks, it demonstrated further acceleration of clearance of amyloid plaques. Majority of patients who were treated at this dose level fell below the threshold of amyloid positivity at 12 weeks.

Trontinemab was also safe and well-tolerated overall, with only one documented case of amyloid-related imaging abnormality (ARIA) indicative of edema, and another such abnormality suggestive of microhemorrhages. Both ARIA cases occurred in the second-highest dose cohort.

These promising Alzheimer’s data follow Roche’s previous failures in the field, which had far-reaching implications for the industry. In June 2022, crenezumab failed a Phase III trial, unable to slow or prevent Alzheimer’s disease in people with healthy mutation who were harboring a specific gene mutation associated with early-onset Alzheimer’s disease.

The monoclonal antibody in 2019 had previously failed two other late-stage trials in early Alzheimer’s, forcing Roche to discontinue both studies.

A few months after crenezumab’s third flop, Roche again stumbled. In November 2022, another investigational Alzheimer’s therapy—ganenterumab—fell short of its primary efficacy endpoints in the GRADUATE I and GRADUATE II studies, which demonstrated that the candidate could not significantly slow clinical decline versus placebo.

During Monday’s investor event, Roche also unveiled long-term data for its investigational antibody prasinezumab showing that the candidate could slow motor progression in Parkinson’s disease. However, Roche was quick to caution that the current data supporting prasinzeumab are still exploratory and need to be verified in independent trials.

https://www.biospace.com/article/roche-plots-neuro-comeback-with-promising-mid-stage-alzheimer-s-data/

Pfizer’s $43B Seagen Buy Starts to Pay Off with Adcetris Phase III Data in DLBCL

 Pfizer on Tuesday released results for the Phase III ECHELON-3 study, demonstrating that the antibody-drug conjugate Adcetris (brentuximab vedotin) significantly boosted survival in patients with relapsed/refractory diffuse large B-cell lymphoma when used with lenalidomide and rituximab.

The pharma did not provide specific data in its announcement, disclosing only that the Adcetris-based regimen led to a “statistically significant and clinically meaningful” improvement in overall survival versus lenalidomide and rituximab plus placebo.

The Adcetris combo also led to “positive outcomes” in various key secondary endpoints, including overall response rate and progression-free survival.

In terms of safety, Adcetris’ tolerability and adverse event profile was consistent with what had previously been established for the antibody-drug conjugate (ADC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

Roger Dansey, chief development officer of oncology at Pfizer, in a statement said that these data from ECHELON-3 indicate that Adcetris “could address an area of high unmet need in patients with relapsed or refractory DLBCL irrespective of CD30 expression.”

“These results are particularly encouraging because the study evaluated heavily pre-treated patients, including some who received prior CAR-T therapy,” Dansey added.

Originally developed by Seagen in collaboration with Takeda, Adcetris is an ADC that targets the CD30 surface protein, which is commonly expressed by certain blood cancers but not healthy cells. According to Seagen’s website, Adcetris carries a toxic payload called monomethyl auristatin E, which it releases inside the malignant cells triggering cell death.

Pfizer secured access to Adcetris in March 2023, when it bought Seagen for $43 billion.

Adcetris was first approved in August 2011 for the treatment of Hodgkin lymphoma and the rare systemic anaplastic large cell lymphoma. The ADC has since picked up several other approvals, allowing its use in other treatment settings and patient populations for these cancers.

The pharma partners are continuing to develop Adcetris in other subtypes and stages of Hodgkin lymphoma, peripheral T-cell lymphoma, non-small cell lung cancer and melanoma.

Tuesday’s readout will help Pfizer further deepen its expertise in ADC technology and expand its footprint in the space. Earlier this month, the pharma laid out its plans for its oncology franchise in the coming years. Key to its new strategy is a refined focus on four cancer types, which include hematologic malignancies such as lymphomas and multiple myeloma.

Pfizer is also looking to build up its biologics business, which it expects to comprise approximately 65% of its cancer franchise by 2030, up from its current 6% mix. The Seagen acquisition, with its deep ADC portfolio, will contribute heavily to potentially meeting this target.

Beyond Seagen, Pfizer in December 2023 also inked a potential $1.05 billion contract with Nona Biosciences to develop the Massachusetts-based biotech’s early-stage mesothelin-targeting ADC HBM9033 in solid tumors.

https://www.biospace.com/article/pfizer-s-43b-seagen-buy-starts-to-pay-off-with-adcetris-phase-iii-data-in-dlbcl/

TB bacteria also present in 90% of those with symptoms who are not diagnosed with TB

 Mycobacterium tuberculosis (Mtb), the bacteria that causes a tuberculosis infection, is present in exhaled breath of 90% of those presenting with suspected tuberculosis. This includes those who were negative on conventional sputum testing and not diagnosed with TB. This raises the possibility that those who have tested negative may be unknowingly transmitting the infection.

Researchers from the University of Cape Town and Amsterdam UMC have analyzed results from over 100 patients who presented themselves to clinics in South Africa. These findings are published in PNAS.

"If someone carries Mtb in their respiratory tract, this may also mean they can spread it. Therefore, since these results suggest a much broader range of people transmitting TB than previously recognized, there are significant implications for public health interventions designed to interrupt transmission," says Ben Patterson, external Ph.D. candidate at Amsterdam UMC and the Amsterdam Institute for Global Health and Development.

Participants in the study attended two community clinics in the southwest of Cape Town before being either diagnosed with TB, or not. Subsequently, aerosol samples were collected in a community-based dedicated TB aerobiology lab using a novel method optimized to find low concentrations of Mtb. These samples were then used to detect the presence of Mtb, finding it in the samples given by 90% of patients, including those that had tested negative by sputum for tuberculosis.

"This rather shatters the paradigm on the transmission of tuberculosis. Previously we understood that Mtb was only expelled by those who have the disease, but this study shows that also those with symptoms who test negative do this and probably spread the infection," says Frank Cobelens, professor of Global Health at Amsterdam UMC and senior fellow at the AIGHD.

Aerosol samplings were repeated at three separate timepoints over six months for all participants. The presence of Mtb decreased in those on treatment as well as—surprisingly—those not on treatment over this time period. Nevertheless, 20% of all participants continued to test positively for Mtb in aerosol after six months. This suggests that transmission can continue over a period longer than previously thought. Indeed, a recent study from the University of Cape Town suggests that tuberculosis could be present in the lungs for up to four years prior to the onset of symptoms.

"Together, our results indicate how complex tuberculosis is, and perhaps also why it is so difficult to eliminate tuberculosis in endemic areas. Even when public health agencies work, according to the current guidelines, effectively against symptomatic TB cases. In this sense, a revaluation of our practices is necessary," adds Cobelens.

More information: Aerosolization of viable Mycobacterium tuberculosis bacilli by tuberculosis clinic attendees independent of sputum-Xpert Ultra status, Proceedings of the National Academy of Sciences (2024). On medRxiv: DOI: 10.1101/2022.11.14.22282157

https://medicalxpress.com/news/2024-03-tuberculosis-bacteria-symptoms-tb.html