Daily Archives: September 4, 2021

MIT engineers, in collaboration with scientists from Brigham and Womens Hospital and Novo Nordisk, are developing a drug capsule technology that could allow the oral delivery of monoclonal antibodies, or other large protein-based drugs that normally have to be injected, for diseases ranging from cancer, to rheumatoid arthritis, to Crohns disease. The new technology is a type of self-injecting capsule, called a liquid-injecting self-orienting millimeter-scale applicator (L-SOMA), which is swallowed, and then effectively injects the liquid medication directly into the stomach wall. In large animal preclinical models, investigators used the technology to deliver four commonly injected medications, including a monoclonal antibody.

Although it is still early days, we believe this device has the potential to transform treatment regimens across a range of therapeutic areas, said Ulrik Rahbek, vp at Novo Nordisk, who, together with Giovanni Traverso, PhD, the Karl van Tassel career development assistant professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Womens Hospital, is co-senior author of the teams published paper in Nature Biotechnology. The ongoing research and development of this approach mean that several drugs that can currently only be administered via parenteral injections (non-oral routes) might be administered orally in the future. Our aim is to get the device into clinical trials as soon as possible, Rahbek noted.

The new L-SOMA technology is described in a paper titled, Oral delivery of systemic monoclonal antibodies, peptides, and small molecules using gastric auto-injectors.

While oral drug delivery is a simple, noninvasive way for patients to take their medicines, most large protein drugs cant be given orally because enzymes in the digestive tract break them down before they can be absorbed. This means that monoclonal antibody therapeutics, and other biologic drugs commonly have to be injected, which isnt so convenient, the authors noted. Oral administration provides a simple and noninvasive approach for drug delivery. However, due to poor absorption and swift enzymatic degradation in the gastrointestinal tract, a wide range of molecules must be parenterally injected to attain required doses and pharmacokinetics their injection-based method of administration often causes healthcare professionals to delay their initiation in favor of less effective oral medications. And patients themselves generally prefer pills, and say their quality of life can be affected when they are prescribed an injectable medication.

Although new technologies for oral delivery of biologic drugs are in development, they have their limitations, which means that they cant be used for some widely used biologics, such as pre-prandial insulin. We recognize today that pills are the preferred route of drug administration, not only for patients, but also for health care providers, Traverso said. If we can make it easier for patients to take their medication, then it is more likely that they will take it, and healthcare providers will be more likely to adopt therapies that are known to be effective Our group focuses on developing systems that make it easier for patients to receive their medications.

Traverso and colleagues have been working on different strategies to deliver biologic drugs orally. In 2019, they developed a capsule that could be used to inject up to 300 g of insulin. The pill, about the size of a blueberry, has a high, steep dome inspired by the leopard tortoise. Just as the tortoise is able to right itself if it rolls onto its back, the capsule is able to orient itself so that its needle can be injected into the lining of the stomach. In theoriginal version, the tip of the needle was made of compressed insulin, which dissolved in the tissue after being injected into the stomach wall.

The new L-SOMS technology described in theNature Biotechnology report maintains the same shape, allowing the capsule to orient itself correctly once it arrives in the stomach. However, the researchers redesigned the capsule interior so that it could be used to deliver liquid drugs, and in larger quantitiesup to 4 mg. This contrasts with their original version, the SOMA, which injects solid medications, but does not work with liquid drugs.

The L-SOMA technology would allow the delivery of liquid medications that need to be absorbed more quickly, or that are challenging to formulate as solids. Delivering drugs in liquid form can also help them to reach the bloodstream more rapidly, which is necessary for drugs like insulin and epinephrine, which is used to treat allergic responses.

The researchers designed their device to target the stomach, rather than later parts of the digestive tract, because the amount of time it takes for something to reach the stomach after being swallowed is fairly uniform from person to person, Traverso suggested. Also, the lining of the stomach is thick and muscular, making it possible to inject drugs while mitigating harmful side effects.

We recognized the potential of liquid injections to readily distribute within the stomachs submucosal plane, thereby accommodating larger dosing volumes than solid dosage forms, the authors commented. Additionally, the increased surface area of interaction between the formulation and the tissuewhen compared to a solid-dose pellet enables accelerated drug pharmacokinetics and pharmacodynamics. Moreover, by targeting the stomach rather than the small intestine, the capsule circumvents the 14 h required for gastric emptying.

The new delivery capsule is filled with fluid and also contains an injection needle and a plunger that helps to push the fluid out of the capsule. Both the needle and plunger are held in place by a pellet made of solid sugar. When the capsule enters the stomach, the humid environment causes the pellet to dissolve, pushing the needle into the stomach lining, while the plunger pushes the liquid through the needle. When the capsule is empty, a second plunger pulls the needle back into the capsule so that it can be safely excreted through the digestive tract.

To evaluate the pills efficacy, researchers tested the L-SOMA devices in pigs, dosing each with one of four treatments, including insulin, epinephrine, adalimumab (a monoclonal antibody used to treat rheumatoid arthritis, Crohns disease, and other autoimmune diseases), and a semaglutide-like GLP-1 analog (an anti-diabetic medication). They then collected blood samples from each of the animals and found that the L-SOMA pill delivered medications at comparable levels to those given with an injection. Delivery of monoclonal antibodies orally is one of the biggest challenges we face in the field of drug delivery science, Traverso said. From an engineering perspective, the ability to deliver monoclonal antibodies at significant levels really transforms how we start to think about the management of these conditions.

They also found that repeated treatments with the L-SOMA dosed with insulin induced the same results, suggesting it may be effective to give multiple, subsequent doses using L-SOMA. The pill achieves a maximum drug plasma concentration similar in magnitude to the standard-of-care subcutaneous injection as quickly as 30 min after dosing and delivers with a calculated absolute bioavailability of up to 80% within a timespan of hours, the team continued. They also found no signs of damage to the stomach lining following the injections, which penetrate about 4.5 mm into the tissue.

The MIT team is now working with Novo Nordisk to further develop the system. Going forward with a view to human testing, the researchers acknowledged that significant clinical development will be required to evaluate safety and effectiveness. Nevertheless, they concluded, These multi-day dosing experiments and oral administration in awake animal models support the translational potential of the system Here we show that the L-SOMA can carry and deliver a broad range of drugs across a range of molecular weights via an oral capsule. In doing so, it can provide a less intrusive route of administration for drugs that are otherwise limited to injectables.

The investigators anticipate that in the future, patients may be able to orally take a diverse array of medications that were once only available via needle. Additionally, because of the L-SOMAs injectable nature, scientists believe that it has the potential to administer vaccines, including the COVID-19 vaccine as well as potentially others.

Traverso and his collaborators continue to explore whats possible with the device. Through the application of fundamental engineering, the type of drugs we can deliver orally is being transformed, Traverso said. It changes how we think about managing different conditions. This technological advancement could apply to chronic conditions that require regular dosing or to systems that are more episodic. Mass administration of an otherwise injectable drug also becomes much easier if it can be given orally.

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Self-Injecting Pill Could Allow Oral Delivery of Monoclonal Antibody and Other Protein Drugs - Genetic Engineering & Biotechnology News

Encouraging data confirming activity in a solid tumor indication presented on first nine patients at low dose cohorts in ongoing autologous CAR-T trial in metastatic castrate-resistant prostate cancer

Three patients showed a greater than 50% decline in prostate-specific antigen (PSA) and concordant PSMA-PET imaging results, including one patient at lowest dose with evidence of complete tumor elimination

Favorable safety profile with modest overall rates of CRS and no neurotoxicity observed

Company to host webcast today to further review results at 11:00am ET

SAN DIEGO, Aug. 31, 2021 /PRNewswire/ -- Poseida Therapeutics, Inc. (Nasdaq: PSTX), a clinical-stage biopharmaceutical company utilizing proprietary genetic engineering platform technologies to create cell and gene therapeutics with the capacity to cure, today announced preliminary results from its Phase 1 clinical trial of P-PSMA-101, the Company's solid tumor autologous CAR-T product candidate to treat patients with metastatic castrate-resistant prostate cancer (mCRPC). These data will be presented at the 6th Annual CAR-TCR Summit virtual meeting at 10:00am ET today in a presentation entitled, "P-PSMA-101 is a High-Tscm Autologous CAR-T Targeting PSMA Producing Exceptionally Deep and Durable Responses in Castration-Resistant Metastatic Prostate Cancer."

Poseida Therapeutics (PRNewsfoto/Poseida Therapeutics, Inc.)

"We are excited about the preliminary data from our Phase 1 trial of P-PSMA-101, which provides further evidence of the effectiveness of our CAR-T platform for solid tumor cancers," said Eric Ostertag, M.D., Ph.D., Chief Executive Officer of Poseida, who will present at the CAR-TCR Summit. "To date, other CAR-T therapeutics have not had much success outside of hematologic malignancies. The deep and durable responses in our trial demonstrate that CAR-T products have the potential to work well against solid tumors, even at low doses, when using the appropriate technology platform."

Efficacy:

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As of the cutoff date, the study had enrolled a total of nine patients with mCRPC: five patients at Dose A who each received a single treatment of 0.25X10E6 cells/kg (an average of about 20M cells), and four patients at Dose B, who each received a single treatment of 0.75X10E6 cells/kg (an average of about 60M cells). All patients received a lymphodepletion regimen consisting of 30 mg/m2 fludarabine + 300 mg/m2 cyclophosphamide. Patients were heavily pre-treated, having received an average of six prior lines of therapy with a median time since diagnosis of 6.4 years.

Key findings included:

- Five patients dosed showed measurable declines in PSA levels- Three patients treated showed a greater than 50% decline in PSA levels and had concordant improvements in PSMA-PET imaging- One patient demonstrated evidence of complete tumor elimination and remains in a durable response of greater than five months at the time of this presentation

"This innovative Poseida PSMA-directed CAR T cell platform has demonstrated a robust anti-tumor response in patients with metastatic castration resistant prostate cancer," commented Susan F. Slovin, M.D., Ph.D., Associate Vice Chair of Academic Administration at Memorial Sloan Kettering Cancer Center and investigator on the trial. "This is the first time that I have seen such impressive responses with an immunotherapy product. The responses of my patients in the trial are far beyond my expectations."

Safety and Tolerability:

P-PSMA-101 demonstrated a favorable safety and tolerability profile. After a previously reported case of Macrophage Activation Syndrome (MAS) exacerbated by patient non-compliance, only three cases of possible Cytokine Release Syndrome (CRS) were observed, which were all low grade (1/2) and were managed well with early treatment. No cases of neurotoxicity (CRES/ICANS) were observed as of the cutoff date.

The Phase 1 trial is an open label, multi-center, 3+3 dose-escalating study designed to assess the safety of P-PSMA-101 in up to 40 adult subjects with mCRPC. The primary objectives of this study are to determine the safety, efficacy, and maximum tolerated dose of P-PSMA-101. Additional information about the study is available at http://www.clinicaltrials.gov using identifier: NCT04249947.

"We believe the key to success in solid tumors is a product with a high percentage of desirable stem cell memory T cells (Tscm)," said Matthew Spear, M.D., Chief Medical Officer of Poseida. "In this study, we have demonstrated that a high-percentage Tscm CAR-T product can home to the bone marrow and, in at least one case, completely eliminate tumor. This bone marrow homing property may be particularly important for bone avid diseases such as prostate adenocarcinoma. Importantly, the favorable tolerability associated with our Tscm CAR-T products has carried over to prostate cancer where we have so far seen manageable cytokine release syndrome and no neurotoxicity."

Company-Hosted Conference Call and Webcast Information

Poseida's management team will host a conference call and webcast today, August 31, 2021 at 11:00am ET. The dial-in conference call numbers for domestic and international callers are (866) 939-3921 and (678) 302-3550, respectively. The conference ID number for the call is 50220147. Participants may access the live webcast and the accompanying presentation materials on Poseida's website at http://www.poseida.com in the Investors section under Events and Presentations. An archived replay of the webcast will be available for 30 days following the event.

Additional CAR-TCR Summit Highlights

Presentation: "Developing CAR-T Cells for Multiple Myeloma: From Autologous to Allogeneic"Session Date/Time: Wednesday, September 1, 2021, 4:00pm ETPresenter: Matthew Spear, M.D., CMO, Poseida Therapeutics

This presentation will outline Phase 1 and 2 development of the Company's lead autologous P-BCMA-101 CAR-T therapy and insights that were used to develop a fully allogeneic version, P-BCMA-ALLO1 that is expected to enter the clinic soon. The presentation will be part of the afternoon session on the Clinical Management Track.

Presentation: "Advancing Nonviral Manufacturing for Multi-Product Allogeneic T-Cell Therapies"Session Date/Time: Wednesday, September 1, 2021, 4:30pm ETPresenter: Devon Shedlock, Ph.D., SVP Research & Development, Poseida Therapeutics

This presentation will discuss how Poseida's piggyBac DNA Delivery System, Cas-CLOVER Site-specific Gene Editing System and Booster Molecule are used to manufacture multi-product, fully allogeneic T-cell therapies. The Company will also discuss how efficient multiplexed Cas-CLOVER gene editing exhibits low to no off-target editing or translocations as determined by next-generation sequencing, and how the Company's Booster Molecule helps to protect against the "allo tax," maintaining a favorable high-stem cell memory T cell (Tscm) product and enabling up to hundreds of doses in a single manufacturing run. This presentation will be part of the afternoon session on the Manufacturing Track.

Presentation: "Developing 'Off-the-Shelf' CAR-T Cells for Bone Marrow Transplant Conditioning"Session Date/Time: Thursday, September 2, 2021, 9:00am ETPresenter: Nina Timberlake, Ph.D., Associate Director, Research (Gene Therapy), Poseida Therapeutics

This presentation will discuss leveraging the piggyBac DNA Delivery System and Cas-CLOVER Site-specific Gene Editing System to generate off-the-shelf fully allogeneic CAR-T cells to specifically target hematopoietic cells in the bone marrow. This potential therapeutic could be used as a non-myeloablative conditioning regimen for hematopoietic stem cell transplant or as a therapeutic for the treatment of acute myeloid leukemia (AML). The presentation will occur as part of the conference's Focus Day, "CAR-TCR Beyond Oncology: Fundamental Biology & Mechanisms of Action Beyond Oncology."

The full presentations at the CAR-TCR Summit will be made available on Poseida's website at their respective session times.

About Poseida Therapeutics, Inc.

Poseida Therapeutics is a clinical-stage biopharmaceutical company dedicated to utilizing our proprietary genetic engineering platform technologies to create next generation cell and gene therapeutics with the capacity to cure. We have discovered and are developing a broad portfolio of product candidates in a variety of indications based on our core proprietary platforms, including our non-viral piggyBac DNA Delivery System, Cas-CLOVER Site-specific Gene Editing System and nanoparticle- and AAV-based gene delivery technologies. Our core platform technologies have utility, either alone or in combination, across many cell and gene therapeutic modalities and enable us to engineer our wholly-owned portfolio of product candidates that are designed to overcome the primary limitations of current generation cell and gene therapeutics. To learn more, visit http://www.poseida.com to connect with us on Twitter and LinkedIn.

Forward-Looking Statements

Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, the potential benefits of Poseida's technology platforms and product candidates, Poseida's plans and strategy with respect to developing its technologies and product candidates, and anticipated timelines and milestones with respect to Poseida's development programs. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. These forward-looking statements are based upon Poseida's current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with development and regulatory approval of novel product candidates in the biopharmaceutical industry and the other risks described in Poseida's filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. Poseida undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

Cision

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Poseida Therapeutics Presents Preliminary Results from Phase 1 Trial of P-PSMA-101 at the 6th Annual CAR-TCR Summit - Yahoo Finance