Category Archives: Gene Medicine

Dive Brief:

Biogen is at a crossroads, awaiting a regulatory decision on the Alzheimer's drug aducanumab by early March that will have wide-ranging implications for the biotech's future.

But while aducanumab's fate hangs in the balance, Biogen has been stocking up on other early-stage assets, aiming to diversify its portfolio beyond risky neuroscience bets. Company executives in 2019 said they were putting more emphasis on ophthalmology and immunology, for instance, and that same year, the company spent $800 million on an acquisition of the eye gene therapy company Nightstar Therapeutics.

ViGeneron offers a novel technology for harnessing adeno-associated virus vectors to treat eye disease. Its vgAAV vectors are designed to get around some of the limits of the standard gene therapy delivery tools and target a variety of different cell types. The two companies noted the technology's potential to more efficiently transduce retinal cells via eye injections, which in theory could lead to more potent treatments.

The company is still fairly new, however, having being spun off in 2017 by Ludwig-Maximilians University in Munich. Its investors include WuXi AppTec and Sequoia Capital China. None of its experimental treatments, led by a gene therapy for retinitis pigmentosa, are in human testing.

The deal is another bet by Biogen on genetic medicine. Earlier this year, the biotech formed a gene editing alliance with Sangamo Therapeutics that could be worth billions of dollars.

Still, investors at the moment are most focused on aducanumab. The roller coaster ride for the drug began in March 2019, when the drug appeared to have failed two clinical trials. Seven months later, however, the company said a further analysis showed significant benefits for a high dose in one clinical trial, and the Food and Drug Administration agreed to review the medicine.

In November 2020, the FDA convened a panel of outside experts, whose review was overwhelmingly negative. Panelists criticized the agency for being too optimistic about Biogen's data and voted near-unanimously against approving the drug.

The committee's vote isn't binding for the FDA, though the agency typically follows its advice. Regulators are due to make their final decision on aducanumab by March 7.

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Biogen pushes further into eye gene therapy with new deal - BioPharma Dive

SALT LAKE CITY It's amazing Cinch Wright is alive.

The little boy got cutting edge gene therapy that replaced disease-causing genes with healthy ones.

It can knock out a gene that's not working right, or add a new gene to the body to help fight disease.

"He loves the dog and the horses and the cows," says Alex Wight about his son.

No doubt about it, Cinch Wight is going to be a cowboy just like his dad.

To date, the FDA has approved four types of gene therapy including one that was given approval just in time for Cinch.

A mandatory newborn screening test at birth revealed Cinch had spinal muscular atrophy or SMA.

"That was the first time I'd ever even heard the term and what it was," said Cinch's mother, Amber.

SMA is a neuromuscular disorder that can paralyze a baby in the first few weeks of life.

"My first thought was, he's never going to be able to ride broncs or anything like that," Alex remembered.

Just one day after Cinch was born, the FDA approved a new gene therapy.

"We were pretty excited to get a phone call from the Department of Health, you know, and have this baby here who we can use this treatment on after its approval," recalled Dr. Russell Butterfield, pediatric neurologist with the University of Utah Health's Intermountain Primary Children's Hospital.

A critical gene in little Cinch was missing.

Dr. Butterfield used an infusion to deliver a virus carrying a new copy of the gene into Cinch's nerve cells.

"It's like a delivery truck to deliver genes to where you want them to go," he explained.

"What that does do, is it stops the disease right where it is."

Just a few years ago, most children born with SMA didn't make it to their second birthday.

"The hardest is holding a baby in one hand and holding that drug in the other and really feeling the weight of that," said Dr. Butterfield.

"And understanding that how different this child's life will be with this new medicine."

Alex Wight has written an inspirational book about his son.

Some might say it's a true story about how real cowboys never give up.

"I wanted to let him know that no matter how hard it gets, as long as he keeps going, he'll be all right," said Alex.

Zolgensma is a new, working copy of a human SMN gene, and makes up for the missing or nonworking survival motor neuron 1 (SMN1) gene, which helps motor neurons work properly. The new gene tells motor neuron cells to produce more survival motor neuron (SMN) protein, which motor neuron cells need to survive and support muscle functions.

Doctors don't know if the one-time infusion will last a lifetime or will have to be repeated and there could be a possible risk of inflammation to the liver that doctors will closely monitor.

The gene replacement therapy costs $2.1 million dollars.

Insurance paid for most of it but Alex hopes sales from his children's book will help pay the rest.

If this story has impacted your life or prompted you or someone you know to seek or change treatments, please let us know by contacting Jim Mertens at jim.mertens@wqad.comor Marjorie Bekaert Thomas at mthomas@ivanhoe.com.

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YOUR HEALTH: New gene therapy saves infant's life - WQAD.com

Durable and Clinically Meaningful Responses Reported from Phase 1/2 Studies of DTX401 for GSDIa and DTX301 for OTC

Phase 3 Studies for DTX401 and DTX301 to Begin in 2021

IND for UX701 for Wilson Disease Submitted; Expect to Enter Clinic in First Half 2021 using AAV Drug Product Made by HeLa PCL Platform

NOVATO, Calif. , Jan. 08, 2021 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development and commercialization of novel products for rare and ultra-rare diseases, today announced positive longer-term safety and efficacy data from the first three cohorts of the ongoing Phase 1/2 studies of DTX401, an investigational adeno-associated virus (AAV) gene therapy for Glycogen Storage Disease Type Ia (GSDIa), and DTX301, an AAV gene therapy for ornithine transcarbamylase (OTC) deficiency. In addition, dosing is nearing completion for the prophylactic steroid cohorts in both studies. Discussions with regulatory agencies continue to progress for both programs, and Ultragenyx expects to initiate Phase 3 studies for DTX401 in the first half of 2021 and for DTX301 in the second half of 2021. The company also plans to start a seamless single-protocol Phase 1/2/3 study for UX701, an AAV gene therapy for Wilson disease.

We continue to see durable and clinically meaningful responses in patients in both the DTX401 and DTX301 programs. GSDIa patients treated with DTX401 demonstrate continually improved glucose metabolism with reduction or elimination of cornstarch dependence over time. OTC patients treated with DTX301 show good metabolic control after tapering or discontinuation of alternate pathway medications and protein restricted diet, saidEric Crombez, M.D., Chief Medical Officer of the Ultragenyx Gene Therapy development unit. With the initiation of the UX701 program in Wilson disease and progression of DTX401 and DTX301 to Phase 3 as well as progress in our preclinical stage programs, we are leveraging our proprietary platforms to advance one of the broadest portfolios of gene therapy programs in the industry.

DTX401 (GSDIa) Program

Phase 1/2 data update: All patients (n=9) responding and demonstrating continued improvement of glucose control while reducing or eliminating cornstarch therapy

All nine patients continue to demonstrate improved glucose control while tapering or discontinuing oral glucose replacement with cornstarch and improvements in energy metabolism pathways over the long term. Patients continue to taper the amount and frequency of cornstarch dosing with progress in eliminating overnight and daytime cornstarch doses. At the primary evaluation timepoint at Week 52, the overall mean reduction in cornstarch was 77% across all three cohorts, including two patients in Cohort 3 showing a reduction of greater than 75%. Longer term follow-up for more than two years for the three patients in Cohort 1 have shown sustained and continued cornstarch reductions with a mean reduction of 91% through weeks 104 and 120. Two patients (one each from Cohort 1 and 3) are completely off cornstarch therapy at weeks 127 and 60, respectively.

Data collected from continuous glucose monitoring (CGM) implemented in Cohort 3 indicate that glycemic control was maintained and even improved despite the reductions in cornstarch dependence. Through Week 48, these patients had decreased cornstarch use by between 30% and 92%. Even with these substantial cornstarch reductions, the patients had a mean 10% increase in the percent of time spent in euglycemia, defined by blood glucose levels in the normal range of 60 to 120 mg/dL.

Additionally, these reductions in cornstarch dosing have had an impact on energy metabolism and body weight. Seven of nine treated patients had decreases of 5% (5.6 kg) to 21% (10.5 kg) in bodyweight following DTX401 treatment, with a mean decrease of 12% from the mean baseline weight of 82.8 kg in these seven patients. The notable weight loss is attributed to improved glycemic control and potentially increased physical activity reported by patients.

Interviews with patients following their Week 24 and/or Week 52 visits provide support for the study results seen to date. Patients reported improvements in both their physical and mental health. This includes increased energy and strength, supporting normalization of daily activities and weight loss, as well as greater mental acuity and reduced stress, with the latter in part noted as related to diminished fears of missing a cornstarch dose. No negative patient feedback has been received to date on their experiences with DTX401.

The safety profile of DTX401 remains favorable; there have been no infusion-related adverse events and no treatment-related serious adverse events reported. All adverse events have been Grade 1 or 2.

All three GSDIa patients dosed in prophylactic steroid cohort doing well with no safety issues

All three patients in a fourth and final Phase 1/2 cohort, which utilizes prophylactic steroids, have been dosed at the same dose as Cohorts 2 and 3. There have been no safety issues through up to 11 weeks post-dosing, and all three patients are doing well and have demonstrated early reduction in daily cornstarch intake.

Phase 3 study of DTX401 in GSDIa expected to initiate in first half 2021

The company has completed Scientific Advice with the European Medicines Agency (EMA) and an End of Phase 2 (EOP2) meeting with the U.S. Food and Drug Administration (FDA) to discuss the Phase 2 data, the Phase 3 design, and endpoints. Based in part on this feedback, Ultragenyx plans to conduct a 48-week Phase 3 study in approximately 50 patients, randomized 1:1 to DTX401 or placebo. All patients in the study will cross over to the therapeutic arm and receive therapy at the end of the initial 48-week follow-up period.

Based on the regulatory discussion and pending finalization, Ultragenyx intends to study as primary endpoints glycemic control by assessing the maintenance of glucose control by CGM and the reduction in cornstarch requirements. These primary endpoints will be supported by key secondary endpoints of improvement in percent of time spent in normal glucose control (60-120 mg/dL), time to hypoglycemia in controlled fasting challenge, and the GSDIa functional assessment diary signs and symptom scale. The durability of the treatment will be supported by the longer-term Phase 1/2 data and early treated Phase 3 patients. Based on the results to date, the therapeutic benefit appears to increase over time during the second year after treatment. Ultragenyx expects to initiate the study in the first half of 2021.

DTX301 (OTC) Program

Phase 1/2 data update: All six previous responders demonstrate durable metabolic control, including greater than two-year sustained responses

As previously reported, six out of nine treated patients responded to DTX301 on a dose-dependent basis, including all three treated at the highest dose. The three complete responders have now been stable through 104, 130, and 156 weeks post-treatment with good ammonia control despite discontinuation of their alternative pathway medications and protein-restricted diets. The three other responders also remain stable through Weeks 52 and 130 and are either continuing to taper medications and diet or intend to continue tapering once COVID-19 restrictions are lifted and patients can be more closely followed in clinic. All responders remain in excellent clinical condition with no significant adverse events, hospitalizations, or other events related to OTC deficiency.

There have been no infusion-related adverse events and no treatment-related serious adverse events reported in the study. All treatment-related adverse events have been Grade 1 or 2.

Prophylactic steroid cohort: Two OTC patients dosed with no safety issues; third patient to be dosed this month

Two of three patients have been dosed in the prophylactic steroid cohort, the final cohort in the Phase 1/2 study, at the same dose as in Cohort 3. Through up to 18 weeks post-dosing, both patients are doing well clinically with good metabolic control and without any safety issues. The third patient in the cohort, who has not yet been dosed due to delays related to COVID-19, is expected to be dosed this month.

Phase 3 study of DTX301 in OTC expected to initiate in second half 2021

Ultragenyx completed the initial Scientific Advice process with the EMA regarding the Phase 3 development plan and continues to have discussions with the FDA regarding the Phase 3 study of DTX301. The EOP2 meeting with the FDA had been delayed and is now scheduled to occur late in the first quarter of 2021.

Based on regulatory feedback to date, the proposed Phase 3 study design will include approximately 50 patients, randomized 1:1 to DTX301 or placebo and followed for 48 weeks initially. The change in 24-hour ammonia levels is expected as the primary endpoint. The entry criteria will allow patients with higher baseline ammonia levels than in the Phase 1/2 study to allow sufficient power to assess the change in ammonia. The primary endpoint will be supported by the change in the rate of ureagenesis as a key secondary endpoint that evaluates the capacity to generate urea from ammonia. Additional secondary endpoints include reduction or discontinuation of scavenger medications and normalization of protein-restricted diet.

The Phase 3 study is expected to begin dosing in the second half of 2021. Placebo patients participating in the study will receive DTX301 at the end of the initial 48-week follow-up period. The company will continue to follow patients in the ongoing Phase 1/2 study during the Phase 3 in order to augment the overall long-term data package supporting the durability of DTX301.

Update on Dose Level Determination Method for DTX301 and DTX401

A new droplet digital PCR (ddPCR) test method has been implemented to determine the level of genome copy (GC) titers for Ultragenyxs gene therapy candidates. This new process improves the accuracy, precision, and specificity compared to the prior quantitative PCR (qPCR) approach. As a result, the actual highest Phase 1/2 dose and planned Phase 3 dose for DTX301 is 1.7 x 10^13 GC/kg (from 1.0 x 10^13 GC/kg) and for DTX401 is 1.0 x 10^13 GC/kg (from 6.0 x 10^12 GC/kg). This change in dose designation of the same product does not represent a change in dose but a more accurate estimate of the actual GC content of the product relative to qPCR, the prior method.

UX701 (Wilson Disease) Program using HeLa PCL Platform

Ultragenyx submitted an Investigational New Drug (IND) application in December as planned for UX701, an AAV9 gene therapy for the treatment of Wilson Disease. The company expects to initiate a seamless single-protocol Phase 1/2/3 study in the first half of 2021. Manufacture and testing of GMP grade drug product to supply the clinical study are complete using the companys proprietary HeLa 2.0 PCL process at the 2,000 liter scale.

Ultragenyx previously reported that UX701 has received orphan drug designation by the FDA. The European Commission has since also granted orphan drug designation for the gene therapy.

Advancing HeLa Producer Cell Line (PCL) Platform and Programs

Ultragenyx continues to advance the proprietary HeLa producer cell line (PCL) platform with recent HeLa 3.0 improvements. The platform enables large 2,000 liter commercial-scale manufacturing and yields high-quality product from a highly reproducible, highly scalable platform, and less expensive process.

Breaking Ground on Gene Therapy Manufacturing Plant

Ultragenyx recently broke ground on its new manufacturing facility to provide important internal capacity to develop and manufacture supply of the companys gene therapies for both clinical-stage and approved products. The initial 100,000 square foot facility will be able to support two independent manufacturing suites with an initial capacity of 30 runs per year and is expected to be complete in 2023.

DTX201 / BAY 2599023 (Hemophilia A) Program Partnered with Bayer AG and Currently Manufactured in HeLa PCL System

Updated Phase 1/2 data through three cohorts were presented at the American Society of Hematology Annual Meeting & Exposition in December 2020 for DTX201 / BAY 2599023, an AAVhu37 gene therapy in development by Bayer, using Ultragenyxs HeLa PCL platform. The data demonstrate dose-responsive and sustained FVIII levels with no evidence of loss of expression through follow-up between 40 and 80 weeks after treatment. Patients in Cohorts 2 and 3 were on FVIII prophylaxis prior to gene therapy, which they have discontinued since approximately 6 weeks after receiving treatment. No spontaneous bleeds have been reported after achieving protective FVIII levels of greater than 15 IU/dL.

No treatment-emergent serious adverse events have been reported. ALT elevations have been observed in three patients at higher doses, which were managed with corticosteroid treatment.

Preclinical HeLa PCL Programs Progress

Earlier-stage preclinical programs utilizing the HeLa PCL platform continue to advance, including:

About GSDIa and DTX401

GSDIa is the most severe genetically inherited glycogen storage disease. It is caused by a defective gene coding for the enzyme G6Pase-, resulting in the inability to regulate blood sugar (glucose). Hypoglycemia in patients with GSDIa can be life-threatening, while the accumulation of the complex sugar glycogen in certain organs and tissues can impair the ability of these tissues to function normally. If chronically untreated, patients can develop severe lactic acidosis, progress to renal failure, and potentially die in infancy or childhood. There are no approved pharmacologic therapies. An estimated 6,000 patients worldwide are affected by GSDIa.

DTX401 is an investigational AAV8 gene therapy designed to deliver stable expression and activity of G6Pase- under control of the native promoter. DTX401 is administered as a single intravenous infusion and has been shown in preclinical studies to improve G6Pase- activity and reduce hepatic glycogen levels, a well-described biomarker of disease progression. DTX401 has been granted Orphan Drug Designation in both the United States and Europe, and Regenerative Medicine Advanced Therapy (RMAT) designation and Fast Track designation in the United States.

About OTC Deficiency and DTX301

OTC deficiency, the most common urea cycle disorder, is caused by a genetic defect in a liver enzyme responsible for detoxification of ammonia. Individuals with OTC deficiency can build up excessive levels of ammonia in their blood, potentially resulting in acute and chronic neurological deficits and other toxicities. It is estimated that more than 10,000 people are affected by OTC deficiency worldwide, of whom approximately 80 percent are classified as late-onset and represent a clinical spectrum of disease severity. In the late-onset form of the disease, elevated ammonia can lead to significant medical issues for patients. Neonatal onset disease occurs only in males, presents as severe disease, and can be fatal at an early age. Approved therapies, which must be taken multiple times a day for the patient's entire life, do not eliminate the risk of future metabolic crises. Currently, the only curative approach is liver transplantation.

DTX301 is an investigational AAV type 8 gene therapy designed to deliver stable expression and activity of OTC following a single intravenous infusion. It has been shown in preclinical studies to normalize levels of urinary orotic acid, a marker of ammonia metabolism. DTX301 was granted Orphan Drug Designation in both the United States and Europe.

About Wilson Disease and UX701

Wilson disease is a rare inherited disorder caused by mutations in the ATP7B gene, which results in deficient production of ATP7B, a protein that transports copper. Loss of function of this copper-binding protein results in the accumulation of copper in the liver and other tissues, most notably the central nervous system. Patients with Wilson disease experience hepatic, neurologic and/or psychiatric problems. Those with liver disease can experience such symptoms as fatigue, lack of appetite, abdominal pain and jaundice, and can progress to fibrosis, cirrhosis, life-threatening liver failure and death. Wilson disease can be treated by reducing copper absorption or removing excess copper from the body using life-long chelation therapy, but unmet needs exist because some treated patients experience clinical deterioration and severe side effects. Wilson disease affects more than 50,000 individuals in the developed world.

UX701 is an investigational AAV type 9 gene therapy designed to deliver stable expression of a truncated version of the ATP7B copper transporter following a single intravenous infusion. It has been shown in preclinical studies to normalize copper trafficking and excretion from the body. UX701 was granted Orphan Drug Designation in the United States and European Union.

About Ultragenyx

Ultragenyx is a biopharmaceutical company committed to bringing novel products to patients for the treatment of serious rare and ultra-rare genetic diseases. The company has built a diverse portfolio of approved therapies and product candidates aimed at addressing diseases with high unmet medical need and clear biology for treatment, for which there are typically no approved therapies treating the underlying disease.

The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyxs strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency and ensuring majority access to its therapies for patients who can benefit.

For more information on Ultragenyx, please visit the companys website at http://www.ultragenyx.com.

Ultragenyx Forward-Looking Statements

Except for the historical information contained herein, the matters set forth in this press release, including statements related to Ultragenyx's expectations and projections regarding its future operating results and financial performance, anticipated cost or expense reductions,the timing, progress and plans for its clinical programs and clinical studies, future regulatory interactions, and the components and timing of regulatory submissions are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, collaboration with third parties, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the effects from the COVID-19 pandemic on the companys clinical activities, business and operating results, risks related to reliance on third party partners to conduct certain activities on the companys behalf, uncertainty and potential delays related to clinical drug development, smaller than anticipated market opportunities for the companys products and product candidates, manufacturing risks, competition from other therapies or products, and other matters that could affect sufficiency of existing cash, cash equivalents and short-term investments to fund operations, the companys future operating results and financial performance, the timing of clinical trial activities and reporting results from same, and the availability or commercial potential of Ultragenyxs products and drug candidates. Ultragenyx undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of Ultragenyx in general, see Ultragenyx's Quarterly Report on Form 10-Q filed with theSecurities and Exchange CommissiononOctober 27, 2020, and its subsequent periodic reports filed with theSecurities and Exchange Commission.

Contact Ultragenyx Investors & MediaJoshua Higa(415) 475-6370

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Ultragenyx Announces Progress Across Broad Gene Therapy Portfolio and Positive Longer-Term Data from Multiple Phase 1/2 Gene Therapy Studies -...

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Senti Bio is at the forefront of using synthetic biology to engineer gene circuits that improve cell and gene therapy products. A gene circuit is an assembly of multi-component genetic constructs specifically designed to program cells to interact with the bodys complex environment using logic to perform desired therapeutic functions. Senti Bio uses these gene circuits to create smarter cell and gene therapies with enhanced therapeutic properties that aim to increase efficacy, precision and control.

Senti Bio is applying its gene circuit technology platform to develop an internal therapeutic pipeline of allogeneic chimeric antigen receptor natural killer (CAR-NK) cells. Senti Bios lead development candidates include next-generation allogeneic CAR-NK cell therapies: SENTI-202 for acute myeloid leukemia (AML), SENTI-301 for hepatocellular carcinoma (HCC), and additional candidates for other undisclosed solid tumor targets.

Leaps by Bayers mission is to invest in breakthrough technologies that may transform the lives of millions of patients for the better, said Juergen Eckhardt, MD, Head of Leaps by Bayer. We believe that synthetic biology will become an important pillar in next-generation cell and gene therapy, and that Senti Bios leadership in designing and optimizing biological circuits fits precisely with our ambition to prevent and cure cancer and to regenerate lost tissue function.

In addition to potentially treating cancer with allogeneic CAR-NK cells, the Senti Bio gene circuit technology platform can be deployed into multiple other cell and gene therapy delivery modalities, across diverse therapeutic areas, such as immunology, neuroscience, cardiovascular disease, regenerative medicine and genetic diseases with the potential to move from treatment to cure.

We are grateful for the support of new and existing investors, including Leaps by Bayer, who believe in our mission of developing gene circuits to program smart cell and gene therapies to improve health outcomes for many people, said Tim Lu, MD, PhD, co-founder and chief executive officer of Senti Bio. Over the past two years, our team has designed, built and tested thousands of sophisticated gene circuits to drive a robust product pipeline, focused initially on allogeneic CAR-NK cell therapies for difficult-to-treat liquid and solid tumor indications. I look forward to continued platform and pipeline advancements, including starting IND-enabling studies in 2021.

Proceeds from the Series B financing will support development of preclinical oncology programs and expansion of the Senti Bio gene circuit technology platform across additional delivery modalities and therapeutic areas. Senti Bio also plans to scale up clinical manufacturing, including process development and design of a cGMP-compliant manufacturing facility for off-the-shelf allogeneic CAR-NK cell product candidates.

The Series B syndicate included existing and new investors as follows: 8VC, Alexandria Ventures Investments, Amgen Ventures, Gaingels, Intel Capital, KB Investment, Leaps by Bayer, LifeForce Capital, LifeSci Venture Partners, Lux Capital, Matrix Partners China, Menlo Ventures, Mirae Asset Capital, NEA, Nest.Bio, Noveus Capital, Pear VC, Ridgeback Capital and Smilegate Investment.

About the Senti Bio Gene Circuit Technology Platform

By combining disciplines from computer science and biology, Senti Bio has designed, built and tested thousands of sophisticated gene circuits that can be deployed into virtually any cell therapy or gene therapy modality. Senti Bios gene circuits are novel and proprietary combinations of DNA that enable cells to sense their environment, perform logic and instruct cells to produce therapeutic proteins for enhanced safety and efficacy. Senti Bio believes that its approach to programming gene circuits in living cells may enable drug developers to build optimal functionality into almost any cell- or gene-based medicine. Senti Bios proprietary platform includes specific gene circuit technologies such as logic gates, small-molecule regulators, combinatorial payloads and synthetic promoters that have the potential to confer greater efficacy, precision and control to cell and gene therapy products. By mixing and matching different gene circuits together, Senti Bio has the ability to create next-generation medicines with enhanced functionality to outsmart disease.

About Bayer and Leaps by Bayer

Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. Its products and services are designed to benefit people by supporting efforts to overcome the major challenges presented by a growing and aging global population. At the same time, the Group aims to increase its earning power and create value through innovation and growth. Bayer is committed to the principles of sustainable development, and the Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2019, the Group employed around 104,000 people and had sales of 43.5 billion euros. Capital expenditures amounted to 2.9 billion euros, R&D expenses to 5.3 billion euros. For more information, go to http://www.bayer.com.

Leaps by Bayer, a unit of Bayer AG, leads impact investments into solutions to some of todays biggest challenges in health and agriculture. The investment portfolio includes more than 30 companies. They are all working on potentially breakthrough technologies to overcome some specific challenges such as, e.g. regenerating lost tissue function, reducing the environmental impact of agriculture, preventing or curing cancer, and others. For more information, go to leaps.bayer.com

About Senti Bio

Senti Bio is a next-generation therapeutics company that is developing gene circuits and programming cells for tremendous therapeutic value. Senti Bios mission is to outsmart complex diseases with more intelligent medicines to transform peoples lives. By programming cells to respond, adapt and make decisions, Senti Bio is creating smarter therapies with computer-like logic, enhanced functionality and greater therapeutic control.

Senti Bio is developing a wholly-owned, gene circuit pipeline focused on allogeneic CAR-NK cells to address major challenges in cancer treatment. Senti Bios lead product candidates include SENTI-202 and SENTI-301. SENTI-202 is a logic-gated allogeneic CAR-NK cell therapy for the potential treatment of acute myeloid leukemia (AML) that more precisely targets and eliminates cancer cells while sparing healthy tissues. SENTI-301 is a combinatorial payload-armed allogeneic CAR-NK cell therapy for the potential treatment of hepatocellular carcinoma. Beyond oncology, Senti Bio plans to leverage its gene circuit technology platform to build other cell and gene therapies that may be of interest to strategic partners across diverse therapeutic areas, such as immunology, neuroscience, cardiovascular disease, regenerative medicine and genetic diseases. For more information, please visit the Senti Bio website at https://www.sentibio.com.

Forward-Looking Statements

This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayers public reports which are available on the Bayer website at http://www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

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Leaps by Bayer Leads USD 105 Million Series B Financing in Senti Bio to Develop Next-Generation Cell and Gene Therapies Using Advanced Gene Circuit...

For Immediate Release: January 04, 2021 Statement From:

Statement Author

Leadership Role

Acting Director - Center for Drug Evaluation and Research

Deputy Center Director for Operations - Center for Drug Evaluation and Research | CDER

Advances in scientific knowledge and drug development technology have provided an opportunity for new approaches to drug development, including the development of drugs for the treatment of rare diseases. These advances have contributed to an increase in development and approval of drugs for the treatment of rare diseases in recent years. In fact, in the past eight years, the U.S. Food and Drug Administration has approved more than twice as many drugs for rare diseases, often referred to as orphan drugs, as in the previous eight years.

For genetic diseases, recent approaches to testing and molecular diagnosis have allowed us to pinpoint, in some cases, the exact cause of a patients disease. For a patient with a very rare genetic disease, development of a drug product that is tailored to that patients specific genetic variant may be possible. This is an important advance in treatment for those with very rare genetic diseases, especially those for which there are no adequate therapies available to treat the disease. Often, these very rare diseases are rapidly progressing, debilitating, and in many cases, can lead to premature death if left untreated.

Developing these products also referred to as n of 1 therapies by some because they are designed for a patient population of one person brings a set of challenges and considerations not seen with the typical drug development process. First, as noted above, the disease is often rapidly progressing, requiring prompt medical intervention. Therefore, development needs to proceed very quickly to have a chance at helping the individual. Second, drug discovery and development for these drug products may be carried out by academic investigators, rather than by biopharmaceutical or pharmaceutical companies. These investigators may be less familiar with FDAs regulations, policies and practices, and less experienced in interacting with the FDA.

At this time, development of individualized genetic drug products is most advanced for antisense oligonucleotide (ASO) products. Therefore, we are taking the first steps in bringing clarity to this emerging area of individualized drug development by releasing a new draft guidance on investigational new drug (IND) submissions for individualized ASO drug products.

The guidance was developed to advise those developing ASO products on an approach to interacting with, and making regulatory submissions to, the FDA. The guidance addresses the following points:

As also discussed in a New England Journal of Medicine editorial in October 2019, we are fully aware that this new drug-discovery paradigm raises many ethical and societal issues that will need to be addressed throughout the process. For example, in these situations, the individuals and their families often function more like drug development collaborators than traditional trial participants. Therefore, it is important to discuss with the individual and family members how effectiveness will be measured. It is also important to ensure that the individual and family members understand the parameters for continuing administration of the investigational drug product before emotions influence decisions, and to recognize that some investigational drug products may fail, or worse, lead to unforeseen side effects.

The FDA understands that well need to work together with the developers of these drug products to bring them safely to patients, and we are willing to engage as needed to address the challenges. For example, for those developing these drug products, it will be important to further understand the required data and information that must be submitted to the FDA so that clinical testing can begin. The FDA is continuing to consider and further develop policy to address some of these issues.

We also are optimistic that development of these individualized drug products may spur gene sequencing that leads to the development of additional individualized drug products for the same disease (though perhaps caused by a different mutation). For this approach to drug development, we need to determine collectively how to effectively bring these drug products to all who need them. If we have the scientific ability to develop drug products for these rare diseases, we need to find a way to bring them to patients while ensuring there is the right balance of risk to benefit. This guidance, which provides clarity on the early development and IND submission process, is the FDAs first step in working with those who are developing these individualized drug products.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nations food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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PENNINGTON, N.J. and SAN DIEGO, Jan. 8, 2021 /PRNewswire/ -- OncoSec Medical Incorporated (NASDAQ:ONCS) (the "Company" or "OncoSec") today announced the first patient was dosed in OMS-104, an investigator-initiated Phase 2 trial evaluating TAVO (tavokinogene telseplasmid), the Company's intratumoral DNA plasmid-based interleukin-12 (IL-12) therapy administered using its gene delivery platform (gene electrotransfer), in combination with the anti-PD-1 checkpoint inhibitor OPDIVO (nivolumab) as a neoadjuvant therapy prior to surgery in patients with operable, locally or regionally advanced melanoma. The trial is designed to evaluate if the addition of TAVO can improve clinical outcomes already observed when using nivolumab alone as a neoadjuvant therapy.

Anti-PD1 checkpoint inhibitors, when administered as a neoadjuvant therapy, have shown encouraging clinical results, but rapid recurrence remains an issue for many patients. TAVO in combination with OPDIVO may drive deep anti-tumor immune responses and complete elimination of tumors prior to surgery, leading to improved long-term clinical outcomes for a significant proportion of treated patients. TAVO in combination with another anti-PD-1 checkpoint inhibitor, KEYTRUDA (pembrolizumab), has already been shown to enhance overall response rate and partial tumor responses in patients with anti-PD-1 checkpoint-refractory metastatic melanoma in OncoSec's KEYNOTE-695 registration directed Phase 2 clinical trial.

"While studies have shown relapse and overall survival advantages when checkpoint inhibitors are given alone following surgery, there is a need to investigate novel immunotherapeutic agents such as TAVO that can be given preoperatively in order to further enhance the clinical efficacy of immunotherapy in patients with advanced melanoma," said Armad A. Tarhini, M.D., Ph.D., Leader of the OMS-104 trial and Senior Member and Professor at the H. Lee Moffitt Cancer Center and Research Institute and the University of South Florida Morsani College of Medicine. "The neoadjuvant approach utilizing TAVO in combination with checkpoint inhibitors as being tested in this study may improve operability, pathologic tumor response and long-term disease control, which is highly desirable for these patients, who continue to have a high risk of recurrence and progression despite the use of standard therapy after surgery."

OMS-104 (NCT04526730) is a Phase 2 open-label, single arm study investigating intratumoral TAVO delivered by gene electrotransfer, or short electric pulses, plus nivolumab as neoadjuvant therapy in patients with operable locally-regionally advanced melanoma. The trial aims to enroll 33 patients and consists of three phases:

1) Neoadjuvant phase, where TAVO will be administered intratumorally using gene electrotransfer in three cycles on days one and eight every four weeks and nivolumab will be administered after TAVO on day eight of each cycle via 30-minute intravenous (IV) infusion;

2) Surgical phase consisting of a definitive surgery that will be scheduled 2-4 weeks after the last dose of nivolumab following radiologic and clinical assessment; and

3) Adjuvant phase, where nivolumab monotherapy will begin 2-4 weeks after surgery and will be administered for up to nine four-week cycles.

The primary endpoint is pathological complete response, estimated based on the proportion of participants with no viable tumor on histologic assessment at definitive surgery after the 12-week neoadjuvant period.

Daniel J. O'Connor, President and Chief Executive Officer of OncoSec, added, "TAVO delivers DNA plasmid-based IL-12 directly into the tumor using gene electrotransfer, which demonstrably enhances the immunogenicity of the treated tumors to yield productive 'in situ' vaccines. This principle has yielded striking results in post-PD-1 patients and is likely relevant in this earlier clinical setting. We look forward to exploring the utility of TAVO as a potential neoadjuvant therapy in a variety of solid tumor settings for patients in need of more effective treatment options."

About TAVOOncoSec's gene delivery technology combines TAVO(tavokinogene telseplasmid), a DNA plasmid-based interleukin-12 (IL-12), with an intra-tumoral gene delivery platform (gene electrotransfer) to achieve endogenous IL-12 production in the tumor microenvironment that enables the immune system to target and attack tumors throughout the body. TAVO has demonstrated a local and systemic anti-tumor response in several clinical trials, including the pivotal Phase 2b trial KEYNOTE-695 for metastatic melanoma and the KEYNOTE-890 Phase 2 trial in triple negative breast cancer (TNBC). TAVO has received both Orphan Drug and Fast-Track Designation by the U.S. Food & Drug Administration for the treatment of metastatic melanoma.

About OncoSec Medical IncorporatedOncoSec Medical Incorporated (the "Company," "OncoSec," "we" or "our") is a late-stage biotechnology company focused on developing cytokine-based intratumoral immunotherapies to stimulate the body's immune system to target and attack cancer. OncoSec's lead immunotherapy investigational product candidate TAVO (tavokinogene telseplasmid) enables the intratumoral delivery of DNA-based interleukin-12 (IL-12), a naturally occurring protein with immune-stimulating functions. The technology, which employs geneelectrotransfer, is designed to produce a controlled, localized expression of IL-12 in the tumor microenvironment, enabling the immune system to target and attack tumors throughout the body. OncoSec has built a deep and diverse clinical pipeline utilizing TAVO as a potential treatment for multiple cancer indications either as a monotherapy or in combination with leading checkpoint inhibitors; with the latter potentially enabling OncoSec to address a great unmet medical need in oncology: anti-PD-1 non-responders. Results from recently completed clinical studies of TAVO have demonstrated a local immune response, and subsequently, a systemic effect as either a monotherapy or combination treatment approach along with an acceptable safety profile, warranting further development. In addition to TAVO, OncoSec is identifying and developing new DNA-encoded therapeutic candidates and tumor indications for use with its new Visceral Lesion Applicator (VLA), to target deep visceral lesions, such as liver, lung or pancreatic lesions. For more information, please visitwww.oncosec.com.

TAVO is a trademark of OncoSec Medical Incorporated.

KEYTRUDAis a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

OPDIVO is a registered trademark of Bristol-Myers Squibb Company.

Risk Factors and Forward-Looking StatementsThis release, as well as other information provided from time to time by the Company or its employees, may contain forward-looking statements that involve a number of risks and uncertainties that could cause actual results to differ materially from those anticipated in the forward-looking statements. Forward-looking statements provide the Company's current beliefs, expectations and intentions regarding future events and involve risks, uncertainties (some of which are beyond the Company's control) and assumptions. For those statements, we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995. You can identify forward-looking statements by the fact that they do not relate strictly to historical or current facts. These statements may include words such as "anticipate," "believe," "could," "estimate," "expect," "intend," "may," "plan," "potential," "should," "will" and "would" and similar expressions (including the negative of these terms). Although we believe that expectations reflected in the forward- looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements. The Company intends these forward-looking statements to speak only at the time they are published on or as otherwise specified and does not undertake to update or revise these statements as more information becomes available, except as required under federal securities laws and the rules and regulations of the Securities Exchange Commission ("SEC"). In particular, you should be aware that the success and timing of our clinical trials, including safety and efficacy of our product candidates, patient accrual, unexpected or expected safety events, the impact of COVID-19 on the supply of our candidates or the initiation or completion of clinical trials and the usability of data generated from our trials may differ and may not meet our estimated timelines. Please refer to the risk factors and other cautionary statements provided in the Company's Annual Report on Form 10-K for the fiscal year ended July 31, 2020 and subsequent periodic and current reports filed with the SEC (each of which can be found at the SEC's website http://www.sec.gov), as well as other factors described from time to time in the Company's filings with the SEC.

Company ContactKim Jaffe, Ph.D.Assistant Vice President, Business Development & Operations+1-858-210-7330 [emailprotected]

Media ContactPatrick Bursey LifeSci Communications+1-646-970-4688[emailprotected]

SOURCE OncoSec Medical Incorporated

http://www.oncosec.com

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OncoSec Announces First Patient Dosed in Phase 2 Trial of TAVO Plus OPDIVO as Neoadjuvant Therapy for Melanoma - PRNewswire