IDEAYA Biosciences, Inc.(NASDAQ: IDYA), a precision medicine oncology company committed to the discovery and development of targeted therapeutics, announced agenda topics for its Investor R&D Day. The webcast event will be hosted by IDEAYA on Monday, December 4, 2023 at 8:00 am to 9:30 am ET.
The presentations by IDEAYA management and key opinion leaders will showcase scientific insights and clinical development opportunities across IDEAYA's synthetic lethality pipeline, including IDE397 (MAT2A) in Phase 2, IDE161 (PARG) in Phase 1, GSK101/IDE705 (Pol Theta Helicase) in Phase 1, and the Werner Helicase program for which an IND submission is planned for 2024. In addition, IDEAYA will highlight its next generation initiatives for MTAP-deletion, that include a wholly-owned program where a development candidate nomination is targeted in 2024 and multiple first-in-class clinical combination opportunities. The IDEAYA Investor R&D Day Webcast agenda will be the following:
Agenda Topics
The Synthetic Lethality Paradigm
IDEAYA Vision, Strategy and Pipeline (Yujiro S. Hata, CEO)
Computational Drug Discovery
Overview of Current Approaches at IDEAYA (Mike White, CSO)
IDE161 Clinical Data and Program Updates (Timothy Yap, MD Anderson)
Emerging Therapeutic Opportunities for MTAP-deletion
Pol Theta Helicase and Werner Helicase Programs (Ramon Kemp, GSK)
Key Opinion Leader Presenters
Timothy Yap, M.D., Associate Professor, Department for Investigational Cancer Therapeutics and Department of Thoracic/Head and Neck Medical Oncology, Medical Director, Institute for Applied Cancer Science, Associate Director of Translational Research, Institute for Personalized Cancer Therapy, M.D. Anderson Cancer Center
Investor R&D Day Webcast Presentation and Registration Information
IDEAYA's Investor R&D Day webcast presentation will be available on the company's website, at its Investor Relations portal (https://ir.ideayabio.com/) in advance of the investor webcast presentation at approximately 6:00 am ET.
The FDA has three target action dates on the books during the next two weeks, including one potentially industry-transforming decision for a CRISPR-based gene therapy.
If approved, exa-cel would become the first CRISPR-edited gene therapy in the U.S. It is intended to be a functional cure for SCD.
Designed to be a one-time, single-dose therapy, exa-cel takes a patient’s own stem cells and genetically edits them using a CRISPR/Cas9 system, enabling them to produce high levels of fetal hemoglobin, which is faulty in SCD. This mechanism of action allows exa-cel to target the hallmark symptom of anemia.
Vertex and CRISPR supported exa-cel’s Biologics License Application, which the FDA accepted in June 2023, with data from a pivotal Phase I/II/III trial and a long-term safety and efficacy study, which together demonstrated that the gene-edited candidate could significantly lessen severe vaso-occlusive events and hospitalizations.
The partners also provided evidence of exa-cel’s safety profile. In November, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee agreed that Vertex and CRISPR had conducted a thorough analysis of exa-cel’s safety, particularly of its off-target effects.
On Nov. 16, the U.K.’s Medicines and Healthcare products Regulatory Agency approved exa-cel under the brand name Casgevy, making it the world’s first CRISPR-based gene-edited therapy.
Arcutis Seeks Approval for Roflumilast Foam in Inflammatory Skin Disease
The FDA is due Dec. 16 to render a verdict on Arcutis Biotherapeutics’ New Drug Application seeking approval for roflumilast foam 0.3% in seborrheic dermatitis.
Roflumilast foam is an investigational, once-daily, non-steroidal topical treatment being developed for a variety of dermatologic indications. It works by blocking the PDE4 enzyme, which is involved in the production of pro-inflammatory mediators. Arcutis is proposing to use this formulation in patients aged nine and above with seborrheic dermatitis, a common inflammatory skin disease.
If approved, roflumilast foam would be “the first topical drug with a new mechanism of action for this condition in over two decades,” Arcutis president and CEO Frank Watanabe said in a statement alongside the company’s announcement of the NDA acceptance.
The application is backed by data from a Phase II study, as well as STRATUM, a pivotal, double-blinded and vehicle-controlled Phase III trial. In STRATUM, roflumilast foam induced an Investigator Global Assessment success rate of 79.5%, as opposed to only 58% in vehicle comparators, an effect that was deemed statistically significant.
Arcutis’ topical treatment also met STRATUM’s secondary endpoints, leading to improvements in itch, scaling and redness. Roflumilast foam was also safe overall, resulting in very few study dropouts due to adverse events.
Roflumilast is approved as Zoryve cream for the treatment of plaque psoriasis in patients six years and older.
Optinose Awaits Verdict on Label Expansion for Xhance
Also on Dec. 16, the FDA is scheduled to release its decision on Optinose’s supplemental NDA, seeking to expand the use of its nasal spray Xhance (fluticasone propionate) to treat patients with chronic sinusitis without nasal polyps.
Xhance is a drug-device combination product that leverages Optinose’s proprietary Exhalation Delivery System to administer an anti-inflammatory agent deep into the nasal cavity, allowing the medication to reach difficult-to-access sinuses and drainage tracts. The product was first approved in September 2017 for the treatment of nasal polyps.
In its supplemental application, which the FDA accepted in May 2023, Optinose provided data from two randomized, double-blinded and placebo-controlled studies. The first, dubbed ReOpen1, enrolled patients with and without nasal polyps, while the second, ReOpen2, focused exclusively on those without polyps.
If approved, Xhance would be the “first-ever drug approved to treat chronic rhinosinusitis,” where there is a “high level” of patient dissatisfaction but “no FDA-approved drug treatments, other than for patients who also have nasal polyps,” Optinose CEO Ramy Mahmoud said in a statement.
With all therecentheadlinesbeing made in genetic medicine, apresentationfrom Turn Biotechnologies announcing the first successful in vivodelivery of messenger RNA to the skin with no off-target effects flew largely under the radar. While Turn Bio will still need to prove its platform in the clinic, the news may mark another step toward surmounting thehurdlesthe industry has faced with delivering RNA therapeutics outside of the liver.
The potential for RNA-based medicines is great. As current small molecule and antibody drugs target only around 0.05% of the human genome, RNA therapeutics—including antisense oligonucleotides (ASOs), small interfering RNA interference (siRNA) and mRNA therapeutics—could significantly broaden the range of druggable targets, if they can safely and accurately reach their destinations.
The discovery a decade ago that the conjugation of GalNac, an amino sugar moiety, to siRNA and ASO drugs could efficiently target the liver was a significant breakthrough for RNA therapeutics. Alnylam’s Amvuttra (vutrisiran), for polyneuropathy of hereditary ATTR (hATTR) amyloidosis, makes use of GalNac delivery, as does Novartis’ Leqvio (inclisiran), which reduces bad cholesterol. The problem, Iris Grossman, chief therapeutics officer at Eleven Therapeutics, told BioSpacelast year, is that very few similar mechanisms have been discovered.
Endosomal Escape and Targeting
Steven Dowdy, a professor of cellular and molecular medicine at the University of California, San Diego, placed the challenges to extrahepatic delivery into two categories. For mRNA therapeutics, the biggest obstacles are specific targeting and immunogenicity, Dowdy told BioSpace. For RNA conjugates like ASOs and siRNAs, he said, the main challenge is endosomal escape.
Steven Dowdy
RNA therapeutics are taken up into the cell by endocytosis, but 99% or more of them are entrapped in an acidified endosome and degraded. The human body has developed natural defenses against RNA-based viruses, making the immune system resistant to foreign RNA. “Our therapeutics look to the body, to cells, like invading RNA,” Dowdy said. Most drug developers ensconce mRNAs in a lipid nanoparticle (LNP), which acts as both a protective shield and an endosomal escape device and allows around 5% of the therapy to make it unscathed into cells. Small RNA therapeutics lack such an endosomal escape device, so only 0.3% to 1% of the conjugate escapes the endosome into the target cell.
In mRNA delivery, Dowdy said, targeting is the rate limiting step. While the APOE protein binds efficiently to the surface of certain LNPs, carrying them to the liver, he said similarly targeted proteins that enable the RNA to reach, say, the pancreas or cardiac myocytes, don’t exist. While chemists are trying to synthesize different types of lipids to bind proteins that would carry the LNP to other cell types, Dowdy said this has proven a difficult problem to solve for highly specific targeting.
The Largest Organ
For Anja Krammer, CEO of Turn Bio, the first objective is to effectively deliver the RNA to the cell itself. To solve this challenge, the company is creating tuneable RNA, which involves precisely delivering cargo to the cell and controlling the expression of the genetic information it carries. “Cells throughout the body and in different tissue types have very different responses and require a different level of delivery,” Krammer told BioSpace. Turn Bio’s pipeline includes investigational therapies for skin wounds, cellular exhaustion and frailty.
Anja Krammer
The second component, she said, is the vehicle that carries the RNA into a specific tissue type. Turn Bio found that carriers used for mRNA vaccine delivery were not effective or efficient enough for therapeutic delivery, so the company developed a proprietary LNP system with its own ionizable lipid.
With vaccines, “you need just a very small amount of reaction in the body to be able to trigger that immune response,” Krammer said. But with a large organ like the skin, “you need to be able to hit a lot of cells, need to be able to transfect a lot of cells, and chances are, you’re gonna need to do it more than once.” Current tissue delivery systems create a lot of immunogenicity due to the PEG lipids used to keep them stable, she added.
Turn Bio’s proprietary approach uses a stabilization system with a controlled release specific to a particular tissue environment. The preclinical data reported in November showed that “we now can contain that delivery within the skin tissue without the uptake into organs” such as the liver and spleen, Krammer said. The company plans to submit an Investigational New Drug application by the end of 2024.
The Central Nervous System
RNAi therapies like Alnylam’s Amvuttra and Onpattro (patisiran)—which both target the liver—work by silencing particular genes that cause or contribute to disease. They do so by degrading the genes’ mRNA.
Vasant Jadhav
Alnylam’s medicines leverage one of two platforms. In the first, siRNA is encapsulated within an LNP and delivered via IV infusion. Onpattro, the company’s first approved drug, for polyneuropathy of hATTR amyloidosis, is delivered in this way. In the second, a modified siRNA is conjugated to a targeting ligand to help it locate a specific cell or tissue within the body. The modifications provide stability against nucleases that would otherwise degrade the siRNA and also help minimize immune recognition of the siRNA, said Alnylam Chief Technology Officer Vasant Jadhav. Alnylam uses two conjugate systems: GalNAc conjugates and central nervous system (CNS)-targeted siRNA conjugates.
Having proven its platforms with Onpattro and Amvuttra, Alnylam is turning its attention to the central nervous system.
“RNAi is not limited to [the] liver,” Jadhav told BioSpace. “RNAi is a naturally occurring mechanism that’s happening in all cells and tissue types.” Some of these are in the CNS, where he said there are many genetically validated targets.
Based on the delivery advances of the past 20 years, “we have highly modified siRNAs that have a targeting or delivery ligand that allows [the therapeutic] to be taken up in CNS,” Jadhav said.
In October, Alnylam announced that its Alzheimer’s disease candidate, ALN-APP, showed sustained pharmacodynamic activity up to 10 months after administration in a Phase I trial. The treatment also led to “marked reductions” in two amyloid fragments implicated in Alzheimer’s and cerebral amyloid angiopathy, according to the company press release.
“We’re really pleased with what we’re seeing in terms of the conjugates going from liver to now achieving this human [proof of concept] with the CNS molecules,” Jadhav said.
The Lungs
Clinical progress is also being made in delivering RNA to the lung. Jerusalem-based SpliSense is targeting a cystic fibrosis mutation with its ASO, SPL84. A short, vector-less single strand of RNA delivered directly to the lung via inhalation, SPL84 is designed to restore the function of the CFTR protein. In a recently completed Phase I study, it was shown to be safe and well tolerated in 32 healthy male volunteers. A Phase II trial, which will test the ASO in 18 cystic fibrosis patients carrying the 3849+10 kb C->T mutation, is slated to begin in the first half of next year.
In a recently published preclinical study, SpliSense demonstrated the potential superiority of its inhaled approach to standard-size LNPs. In the study, which tested SPL84 in mouse and monkey lungs, the authors wrote that the candidate diffuses more effectively than these LNPs, primarily due to its small size.
In comparison to Vertex and Moderna, whose CF program, VX-522, uses a LNP for delivery, SpliSense CEO Gili Hart said her company’s approach is “one hundred times more effective in relation to migration in the lungs.”
In an interview last year, Ashley Mahoney, director of external communications at Vertex, told BioSpace that the company had successfully identified an LNP that can deliver the CFTR mRNA to target cells at levels that result in CFTR function levels associated with clinical benefit.
While he declined to hazard a guess as to the next organ to see successful RNA delivery, Dowdy said: “If and when we solve the endosomal escape problem in a safe manner, that will open up the ability of RNA therapeutics to selectively treat . . . cancer, COVID and a multitude of other diseases.”
Millions of people living with neurodegenerative diseases and their loved ones have long hoped for the day when treatments could change the prognosis from an inevitable decline to a managed, stable condition. The urgent need for life-changing therapies exists against the backdrop of a growing prevalence of Alzheimer’s disease, Parkinson’s disease and other progressive disorders.
Neurodegenerative diseases are historically difficult to treat and effective therapies have eluded even the most dedicated scientific minds for decades. However, scientific innovation in neurology and a growing understanding of underlying disease pathology is opening the door to novel pathways to treat, and potentially cure, myriad diseases.
Gene Therapy: Targeting the Cause
More and more, scientists are identifying and developing ways to treat the fundamental cause of certain neurodegenerative diseases rather than merely treating the symptoms. Take, for example, a disease like frontotemporal dementia (FTD), which, in some cases is caused by a single genetic defect. In up to 10% of people with FTD—a disorder that affects the frontal and temporal lobes of the brain and is one of the most common causes of early-onset dementia—the disease is caused by a mutation in the granulin gene. The defective gene creates a deficiency of progranulin, a complex and highly conserved protein thought to play several critical roles in lysosomal function.
With the potential to correct the defect at its source by delivering a functional copy of the gene that is mutated, nonfunctional or missing, gene therapy could be a powerful treatment approach.
As in many genetic disorders, delivery is a critical aspect of developing gene therapies for neurodegenerative diseases. Precise approaches that deliver one-time treatments directly to the brain and address the root cause of the disease have shown promise.
The blood-brain barrier and potential off-target effects have made traditional drug development especially difficult for neurodegenerative diseases. But a gene therapy delivered directly to the cerebrospinal fluid (CSF) surrounding the brain and spinal cord has the potential to overcome these limitations and achieve long-term correction of these illnesses.
In the case of FTD, once delivered, a new gene may confer stable, long-term expression of the required protein, offering effective, long-term disease-modifying treatment. There is also the potential benefit of cross-correction, where the protein is secreted into the interstitial fluid and CSF, possibly expanding the benefits to cells beyond those directly transduced. If this secreted protein can confer general neuroprotective effects, gene therapy could be a transformative treatment option for a range of neurodegenerative diseases—even those not caused by a specific genetic defect.
Accessing the Brain With AAV Delivery
In order to reach a broad range of tissues, including hard-to-target organs like the brain, many gene therapy developers are taking advantage of the leading viral vector platform: adeno-associated viruses (AAVs). Wildtype AAVs, which are not known to cause human disease, are one of the most promising in vivo tools for delivering a functional copy of a gene to cells in both the central nervous system and periphery.
The strength and versatility of AAV-based vector technology has contributed significantly to the FDA approval of several gene therapies. Today, eight such therapies are on the market for a range of indications. Notably, Novartis broke new ground in the treatment of spinal muscular atrophy, a rare neuromuscular disorder, with the 2019 approval of Zolgensma. This one-time gene therapy targets the genetic root cause of SMA by replacing the function of the missing or nonworking SMN1 gene, halting progression of the disease.
A gene therapy program being developed by my company, Passage Bio, is focused on the treatment of FTD with granulin mutations, for which there are currently no approved disease-modifying therapies.
Passage’s global Phase I/II clinical trial is evaluating PBFT02, an AAV-delivery gene therapy candidate that uses a differentiated approach to directly target the CNS via intra-cisterna magna (ICM) administration. In ICM administration, therapy is delivered directly to the CSF via injection into the cisterna magna, an area outside of the brain near the base of the skull.
The Pursuit of Transformative Medicines
The work underway at Passage is a mere snapshot of the many positive advancements happening across the field. Genetic medicines continue to demonstrate their ability to dramatically improve lives. There are currently hundreds of promising gene therapy programs in various stages of development, many of which are producing encouraging clinical data.
The progress is palpable, but challenges remain. The pursuit of science is filled with twists and turns. Just like the development of a small molecule, a gene therapy program is only as promising as its clinical data—and every program is truly unique. That’s why Passage and other companies seeking solutions for individuals with neurodegenerative diseases must have a razor-sharp focus on clinical execution to generate impactful results that will improve the lives of these patients and their families.
On Friday, shortly after Powell failed to hammer the hawkish case in his "fireside" chat with stocks eager to take out 2023 highs, we said that Powell has a big problem on his hands not so much because if the market was indeed correct about imminent easing that only assures that inflation will come back with a vengeance and Powell would indeed be the "second coming" of a former Fed Chair - only Burns not Vlcker -but because the kneejerk surge higher in gold (and digital gold) meant that the once again deathwatch for the dollar - and fiat in general - had resumed.
Well, with futures having opened for trading on Sunday night, what we joked about on Friday, namely that Powell - having seemingly once again lost control of the hawkish narrative - may be leaking emergency rate hikes though Nick Timiraos on Dec 12, ahead of the December FOMC (now that the Fed is in blackout mode)...
