In Vivo Scientist Sarah DeVos at Denali named as author on Tau IP just issued for Sangamo. She was working with Brad Hyman at Mass General 25 or so open positions many related to clinical trials. Pipeline includes ALS, Parkinsons, Alzheimers related Exec team out of Genentech 3 P1 Takeda partner
Denali Therapeutics: An IPO Trap Or Something More? Jan. 6, 2018 8:18 AM ET|12 comments | About: Denali Therapeutics, Inc. (DNLI), Includes: TKPYY This article is now exclusive for PRO subscribers. Zach Hartman Zach Hartman Biotech, healthcare, Deep Value, contrarian Invest Against Cancer Summary Denali Therapeutics presents one of the most jaw-dropping cash positions I've yet encountered in such an early-stage pharma company.
The company is aiming huge in neurodegenerative disorders, and they may just have enough runway to actualize development.
The risk of trial failure remains ever-present, as it goes with neurodegenerative drug development. This could leave shareholders holding the bag.
It's always exciting to see fresh faces in the markets, unblemished by years of bag holding and promises unkept. When a new biotech commits to an IPO, as did Denali Therapeutics (DNLI) late last year, it offers new hope for investors and patients alike.
In the case of DNLI, this amounted to an initial IPO valued at some $287 million. And the company is now worth over $1 billion, despite having a very early-stage clinical pipeline.
Is it justified? Should you take the dive? This is what we're all clamoring to know. So today I want to take a deeper look into some of the science and immediate prospects of DNLI.
The flagship: Targeting the lysosome for neurodegenerative disease Currently, DNLI's most advanced agent is an inhibitor of the leucine-rich repeat kinase 2 (LRRK2), DL201. A second LRRK2 inhibitor, DNL151, is being investigated outside the United States.
Why is LRRK2 an important drug target? In Parkinson's disease, mutation of LRRK2 appears to be at the center of activating events that trigger inflammation, aggregation, and brain cell death. And targeting LRRK2 has been shown to provide protection of neuronal activity in in vitro models of Parkinson's disease. However, to date, the LRRK2 inhibition hypothesis has failed to yield an effective therapy.
Not long after acquiring the drug from Roche (OTCQX:RHHBF), DNLI initiated a phase 1 trial for DL201 in June 2017 for the treatment of Parkinson's disease. In their prospectus, the company listed a clinical hold placed on the trial to place an exposure cap due to findings of preclinical toxicity. However, this hold has since been lifted, and DNLI anticipates having preliminary data from this study in 2018.
DNL151 is being investigated in early-stage study in The Netherlands, and DNLI expects to make a decision about which drug to continue developing as results are described.
Financial considerations At the time of their IPO, DNLI held $190 million in cash and equivalents. Then they raised an additional $280 million as part of their initial funding round, placing them in the enviable position of having nearly a half billion dollars worth of cash in the tank. In their prospectus, DNLI disclosed total operational expenditures of $87.4 million in 2016, with 2017 on track to follow that figure pretty closely.
Obviously, this is a rather aggressive burn rate, but it's heartening to me that the bulk of the expenses are being plowed into research and development. With just the cash they've raised and held as of their IPO, DNLI holds somewhere around 5.5 years worth of cash for their runway.
But then came even more help in the financial department: Takeda (OTCPK:TKPYY) entered the fray with a deal valued at upwards of $1 billion to co-develop an entire neurodegenerative disease platform for Alzheimer's disease.
In this arrangement, TKPYY fronted $40 million and purchased another $110 million of stock at $26.10 per share, bolstering DNLI's coffers even further and providing almost 2 more years of cash runway. In return, TKPYY gains the right to option any one of three drugs currently under development as part of the partnership, with DNLI incurring the costs and study leading up to an IND submission.
DNLI is eligible for up to another $1 billion in regulatory and sales milestones, although this would require TKPYY to exercise their options on all three of the drugs in development.
Risks and reward DNLI offers a very interesting, already highly valued prospect for speculative investors. If things go well, then the 7+ years of cash runway the company holds could very well be enough to carry through either DLN201 or DLN151 through clinical trials. And as they cull developmental programs, I suspect that they'll be able to keep their burn rate relatively stable throughout development.
Still, these are neurodegenerative disorders, and at any point in development, these promising new agents could join a massive graveyard of therapeutic hopes. To date, pharmaceutical development has struggled to improve upon symptomatic treatment for Parkinson's disease, and nothing approaching a cure has yet been discovered.
Will the LRRK2 inhibitor approach bear fruit here? It's impossible to tell at this time, and you can bet that I'll be watching for news of these trials very closely.
There is a similar case in Alzheimer's disease, where very few true innovations have been put forward by the industry.
My point, overall, is that these are tough diseases to treat, and they represent massive risk and reward for any company attempting to develop therapies. To me, this is where the principal risks lay: the therapy graveyard.
This is the first biotech security where I've looked and said to myself, "They are in incredibly early days, and I'm NOT worried about their cash position." But I will always worry about a company pursuing neurodegenerative disorders. They are just that tough a nut to crack.
But someone's going to crack this nut eventually. The DNLI approach might be a major leap forward for these diseases. If that's the case, then the current $1.5 billion market cap (as of this writing) is a huge bargain.
Conclusions It is clear that DNLI presents something worth paying attention to. They got a big pharma to open their pocketbooks at a very early stage. They executed a successful initial fund raise. They have the cash. They have a pipeline.
But will they get a marketable drug? That's the ten-billion-dollar question. My advice to investors at this point would be to keep a close watch on DNLI, but I would stay my hand at this time from buying. There is plenty of time to see whether there's any hope for the phase 1 trials.
However, I can't fault the people who are interested in getting in as close to the ground floor as possible. But there's always the possibility that we'll see the company seem to languish as trial results are anticipated. Caveat emptor, as always, but DNLI is clearly no fly-by-night show.
Denali to Test Higher Doses of Potential Parkinson’s Therapy on Healthy Volunteers, With FDA’s Blessing
JANUARY 3, 2018 Patricia Inacio, PhDBY PATRICIA INACIO, PHD IN NEWS.
Denali to Test Higher Doses of Potential Parkinson’s Therapy on Healthy Volunteers, With FDA’s Blessing
Denali Therapeutics says its experimental therapy for Parkinson’s disease, DNL201 — a small-molecule inhibitor of leucine-rich repeat kinase 2 (LRRK2) — stopped an average 90 percent of LRRK2 kinase activity at its highest concentration. When the drug’s levels dropped to the lowest concentration (known as trough levels), it still inhibited on average 50 percent of such ctivity.
The U.S. Food and Drug Administration (FDA) reviewed the results of Denali’s ongoing Phase 1 trial and, along with additional preclinical data, decided to remove the partial clinical hold it had placed on DNL201 in April 2017. At that time — following Denali’s investigational new drug application to test DNL201 in humans — the FDA had imposed an “exposure cap” based on preclinical toxicity study findings.
Mutations in the LRRK2 gene that increase the activity of this enzyme have been linked to a high risk of Parkinson’s, due to a LRRK2-increased risk of neuron death.
The ongoing Phase 1 trial aims to test DNL-201 among healthy volunteers in three phases. In Part 1, six patients received a single ascending dose of DNL-201 – 10, 30 and 60 mg – and two patients received a single placebo dose. In Part 2, eight patients received a 40 mg dose once or twice daily for 10 days; two other patients received placebo twice daily.
The San Francisco-based company has finished dosing Part 1 and 2. Now, with the FDA’s decision to lift the partial hold, Denali will test stronger doses to achieve higher levels of LRRK2 inhibition.
Researchers assessed LRRK2 inhibition by measuring blood-based biomarker assays, and detected DNL-201 in patients’ cerebrospinal fluid, indicating that the drug had penetrated the central nervous system.
Denali is developing a second inhibitor of LRRK2, called DNL-151, and is now testing that therapy in a Phase 1 clinical trial of healthy volunteers in the Netherlands. The results of both Phase 1 trials will determine which therapy will move forward and undergo testing in Parkinson’s patients.
“Mutations in LRRK2 are a major risk factor for Parkinson’s disease. Targeting this degenogene [those that when mutated cause, or are major risk factors for, neurodegenerative diseases] represents a promising approach to develop disease modifying medicines for patients suffering from this terrible disease,” Denali CEO Ryan Watts said in a press release.
“By restoring LRRK2 activity to normal levels, we believe we can reverse lysosomal dysfunction, which could potentially benefit both patients with LRRK2 mutations, as well as idiopathic Parkinson’s patients who exhibit lysosomal dysfunction,” he added.
Added the company’s chief medical officer, Dr. Carole Ho: “Our robust biomarker assay allows us to establish and monitor LRRK2 target and pathway engagement, and assess the exposures required to reach desired target inhibition. We have demonstrated significant inhibition of LRRK2 kinase activity with DNL201, which gives us confidence to proceed with further clinical testing.” ------------------------------------------- Phase I data for its LRRK2 inhibitor DNL201 to treat Parkinson’s Disease is due by June 30th
Denali CEO Ryan Watts Denali Therapeutics What're they building in there?
CEO: Ryan Watts Based: South San Francisco Founded: 2015 Clinical focus: Neurodegeneration Company website
The scoop: As head-turning company launch announcements go, it's hard to top coming out of stealth with a $217 million Series A fundraise. And, upping the ante, Denali Therapeutics is putting that money toward finding new treatments for Alzheimer's disease, a field that has long bedeviled biopharma and has an R&D rap sheet littered with decades of failure. But the group of Genentech veterans behind Denali believe they have the ideas and experience to change the narrative in neurodegenerative disease with an ambitious effort to advance multiple clinical candidates.
What makes Denali Therapeutics Fierce: The company made its glitzy debut about four months ago and has essentially maintained radio silence ever since. At launch, Denali's story boiled down to this: A trio of neuroscience experts with stints at Genentech in common had grown frustrated with the industry's tepid approach to neurodegeneration, characterized by hedged bets on individual drugs for broad populations. In contrast, Denali wanted to take a sweeping approach to the field, spotlighting recently discovered genetic drivers of disease and then diving into translational research to see where the science takes them. That pitch caught the attention of some A-list biotech investors, and thus a record-setting fundraise was born.
Now the company is divulging a few more details about its plans without compromising the commitment to confidentiality that CEO Ryan Watts said is key to how Denali does business.
Starting with Genentech: The story of that company's success, told in brief, hinges on the discovery of the molecular mechanisms that differentiate various cancers once thought to be monolithic. Homing in on the genetic drivers of tumor growth, the company developed revolutionary targeted treatments that changed the standard of care. That, more or less, is what Denali wants to do in neuroscience, Watts said. The neurodegeneration field is about a decade behind oncology, but the ongoing discovery of the so-called degenogenes that drive cognitive decline has spotlighted promising new therapeutic targets, he said.
The industry has a long record of failure in the likes of Alzheimer's and Parkinson's diseases in part because recent projects have "lacked this translational rigor that we had in oncology," Watts said, pressing into Phase III with a make-or-break asset and few if any validated biomarkers to adequately measure progress. That model often disincentivizes researchers to get to what Watt calls "the key experiment." If your solitary drug doesn't actually move the needle on its biological target, you don't have a company anymore.
Denali wants to do things differently. Instead of buckling down on a single candidate, the biotech is developing about a dozen, focusing on intracellular trafficking pathways, inflammation, axon degeneration and synapse elimination, among other areas. "There are many targets to harvest now," Watts said, and Denali has identified four of those programs as core assets. The company isn't disclosing any more details about the science behind its pipeline, and Watts declined to specify a timeline for getting into the clinic, saying only that Denali wants to do so "sooner than later."
But Denali will say that it plans to build a wide portfolio of first-in-class treatments for neurodegeneration, advancing on multiple fronts with the help of its unspecified academic collaborators. The goal, in short, is to become the Genentech of neuroscience, an admittedly lofty ambition that helped inform the company's name, Watts said.
Such an expansive approach to neurodegeneration requires a lot of capital and some patient investors, and Denali has both. That combination frees up management to recruit the necessary talent, Watts said, and the company recently added fellow Genentech veterans Carole Ho, as chief medical officer, and Steve Krognes, who serves as chief financial officer. Denali has a staff of about 20, and the company is looking for drug hunters to fill out its ranks, Watts said, scouting for scientists who can match its commitment to finding new therapies.
"We're in it for the long haul," he said. "This is our life's work."
Investors: Fidelity Biosciences, ARCH Venture Partners, Flagship Ventures, the Alaska Permanent Fund and undisclosed others
Collaboration uses AbCellera’s high-throughput single-cell screening capabilities to find new antibodies against a target identified by Denali linked to neurodegenerative disorders. Vancouver, Canada (June 12, 2018) - AbCellera Biologics Inc. today announced the successful completion of the first phase of its collaboration with Denali Therapeutics Inc. (NASDAQ: DNLI). Under the collaboration, AbCellera applied its single-cell screening technology to discover hundreds of novel monoclonal antibodies with specific binding properties against a genetically-validated target for neurodegenerative disease.
Denali’s CEO, Ryan Watts, Ph.D., commented, “We are thrilled to collaborate with AbCellera to discover biologics candidates that leverage our proprietary Antibody Transport Vehicle (“ATV”) to cross the blood-brain barrier and that could ultimately benefit patients suffering from neurodegenerative diseases. We are impressed with the AbCellera team’s expertise and approach.”
AbCellera performs ultra-deep screening of natural immune repertoires from any species to discover antibodies from millions of single cells per run, including plasma cells, B-cells and antibody-secreting cells. AbCellera’s platform supports a wide array of single-cell antibody selection assays, combining multi-step and multiplexed binding measurements, and live-cell assays. The combination of speed, screening depth, and greater specificity generates thousands of high-quality antibodies, and translates to successful discovery against difficult targets such as membrane proteins, GPCRs and ion channels.
Beyond its core microfluidic screening technology, AbCellera capabilities integrate expertise in animal immunizations for any species (including humanized rodent platforms), assay design, bioinformatic analysis using a proprietary suite of software and visualization tools, and antibody characterization for developability and engineering. The approach has been validated in multiple partnerships with pharmaceutical and biotechnology companies, proving successful when other technologies, including hybridoma, display technologies and emerging B cell selection platforms, have fallen short.
“This partnership exemplifies our commitment to work with companies at the forefront of innovation in antibody therapeutics. Neurodegenerative disease is one of the most important frontiers for biologics. It is also one of the most challenging, and bringing new therapies to patients will require the best possible technologies on every front.” commented Carl Hansen, CEO of AbCellera. “The speed and success of this project highlight what can be achieved when companies work closely together and share complementary technologies. It has been an absolute pleasure working with the Denali team and we are excited to be providing innovation that enables their most demanding discovery programs.”
Financial terms of the collaboration were not disclosed.
About AbCellera Biologics Inc.
AbCellera is a privately held company that engages in partnerships to discover and develop next-generation therapeutic antibodies. AbCellera’s single-cell platform integrates end-to-end capabilities for therapeutic antibody discovery through a combination of technologies including proprietary immunizations, microfluidics, high-throughput imaging, genomics, computation, and laboratory automation. Ultra-deep screening of single B cells allows unprecedented access to natural immune responses, enabling rapid isolation of large and diverse panels of high-quality lead antibodies from any species, including humans.
About Denali Therapeutics
Denali is a biopharmaceutical company developing a broad portfolio of therapeutic candidates for neurodegenerative diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the blood-brain barrier and guiding development with biomarker monitoring to demonstrate target engagement and select patients. Denali is based in South San Francisco. For additional information, please visit www.denalitherapeutics.com
On August 24, 2016, we entered into a License and Collaboration Agreement, or the Collaboration Agreement, with F-star. The goal of the collaboration is the development of Fcabs to enhance delivery of therapeutics across the BBB into the brain. The collaboration leverages F-star’s modular antibody technology and our expertise in the development of therapies for neurodegenerative diseases.
Under the terms of the Collaboration Agreement, we can nominate up to three Fcab targets, or Accepted Fcab Targets, within the first three years of the date of the Collaboration Agreement; and we have selected TfR as the first Accepted Fcab Target. With respect to each Accepted Fcab Target, we can nominate up to eight Fab targets, or Accepted Fab Targets, which are targets bound by the variable domains of an antibody or other therapeutic modalities, or Fabs. Under the terms of the Collaboration Agreement, we paid F-star Gamma an upfront fee of $5.5 million, which includes selection of the first Accepted Fcab Target under the Collaboration Agreement. We are obligated to pay a one-time fixed fee in the low single-digit millions for each additional Accepted Fcab Target we select, technical milestone payments for each Accepted Fcab Target, up to a maximum of $15.0 million in the aggregate for all Accepted Fcab Targets, and, at specified times, monthly exclusivity fees for Accepted Fcab Targets and Accepted Fab Targets, which may be eliminated in certain circumstances. We are also responsible for certain research costs incurred by F-star in conducting activities under each agreed development plan, for up to 24 months. These research costs for the agreed TfR development plan will be up to $2.1 million.
In connection with the entry into the Collaboration Agreement, we also purchased an option for an upfront option fee of $0.5 million, or the buy-out option, to acquire all of the outstanding shares of F-star Gamma pursuant to a pre-negotiated buy-out option agreement, or the Option Agreement. If we exercise this buy-out option, we will be required to make initial exercise payments ranging from, in the aggregate, approximately $18.0 million to $50.0 million, plus a payment for the estimated net cash held by F-star Gamma at the time of such exercise. In addition to these initial exercise payments, we would be required to make certain contingent payments upon the achievement of certain preclinical, clinical, regulatory and commercial milestones, up to a maximum amount of $447.0 million in the aggregate. The amount of the initial exercise and contingent payments varies based on whether F-star delivers an Fcab that meets pre-defined criteria, whether the Fcab has been identified solely by us or solely by F-star or jointly by us and F-star and the timing of our exercise of the buy-out option. Following exercise of the buy-out option, we will not be required to make any further milestone or royalty payments under the Collaboration Agreement.
We recognized the entire $5.5 million upfront fee in research and development expense for the year ended December 31, 2016. We recognized an additional $0.3 million of research and development expense related to the funding of F-star Gamma research costs during the year ended December 31, 2016. ============================== F-star Announces Collaborative Agreement with Denali Therapeutics for the Development of a Multispecific Antibody Platform to Deliver Therapeutics Across the Blood-Brain Barrier
Cambridge, UK and South San Francisco, USA – 25 August 2016 – F-star, a biopharmaceutical company developing novel bispecific antibodies, announces a collaborative agreement with Denali Therapeutics Inc. (Denali), a biotechnology company focused on neurodegenerative disorders, to research and develop antibodies for the delivery of medicines across the blood-brain barrier (BBB) into the central nervous system (CNS).
The collaboration will leverage F-star’s Modular Antibody TechnologyTM and Denali’s expertise in the development of therapeutics for neurological diseases to generate FcabsTM (constant Fc-domains with antigen-binding activity) which can bind to transporters in the BBB. Using the “plug-and-play” properties of the platform, these Fcabs can be rapidly inserted into any existing antibody to generate a full size bispecific antibody (mAb² TM) which can both cross the BBB, as well as bind to specific targets within the CNS. This mechanism has the potential to treat neurological diseases by acting on specific targets in the brain.
The agreement is with F-star Gamma Limited (F-star Gamma), a new Asset-Centric Vehicle in the F-star family. Under the agreement, Denali will make upfront payments to F-star totalling $6 million. Denali has the option to nominate a pre-specified number of Fcab targets. F-star Gamma will also receive research funding and is eligible for technical milestone payments. In addition, Denali also has the option to acquire F-star Gamma prior to the initiation of the first Phase 1 clinical trial in return for aggregate exercise and milestone payments to the F-star Gamma shareholders of up to $450M in total. If Denali does not exercise the option to acquire F-star Gamma, it has the right to license a pre-specified number of mAb² based on each Fcab generated by F-star Gamma, in return for license fees, development, regulatory and commercial milestones payments with a potential aggregate value of $1B and tiered royalties on product sales. John Haurum, CEO of F-star, commented: “Our Modular Antibody Technology is ideally suited to deliver biologic drugs into the Central Nervous System across the blood-brain barrier. Denali’s scientists are world leaders in understanding the complex mechanisms of the blood-brain barrier and we look forward to collaborating with the team to unlock the potential of our platform and develop more efficient treatments for neurological disorders.” ========================= Denali acquires F-star's blood-brain barrier bispecific antibody tech in deal worth up to $471M by Amirah Al Idrus | May 30, 2018 4:54pm
Bispecific antibodies do more than target two antigens—they are designed to do so in a way that improves upon an approach that simply combines two monospecific antibodies. (rawpixel) eurodegenerative disease biotech will hand over $24 million up front, the company said in a statement. F-star stands to earn an additional $447 million in milestone payments. It plans to use the proceeds from this deal to bankroll its pipeline of immuno-oncology bispecific antibodies. While it hasn't disclosed specific indications, it has a range of programs "in various stages of preclinical development," said CEO John Haurum. One candidate, targeting a pair of checkpoint molecules, LAG-3 and PD-L1, recently entered phase 1.
F-star's Modular Antibody Technology makes bispecific antibodies by introducing a new antigen binding site to the constant (Fc) region of an antibody. This binding site, dubbed an Fcab (Fc domain with antigen binding ability), in addition to the antibody's own binding domain, allows it to bind to two different antigens.
"The way we approach it from a drug-hunting point of view is looking for compounds where a bispecific modality provides more than just A plus B," Haurum said. "It's not a matter of putting activity A together with activity B—it's a matter of finding bispecific compounds with a synergy between the two and improving upon what you can achieve with combining two monospecific ones."
Under the original agreement, Denali would use F-star's tech to create Fcabs that can bind to transporters in the blood-brain barrier (BBB). It had the option to acquire F-star Gamma before the initiation of the first phase 1 clinical trial of an Fcab developed under the collaboration, but has chosen to ramp up the timeline.
"Our decision to exercise the option to buy F-star Gamma reflects the progress in our collaboration with F-star and the generation of preclinical data showing that our proprietary TV platform technology may enable us to deliver biologics across the BBB and into the brain. Specifically, recent data demonstrated robust and sustained peripheral and brain activity for our ETV:IDS program for Hunter Syndrome and hence preclinical proof of concept. Furthermore, the expanded collaboration allows us to deepen and broaden our research efforts supporting our TV platform technology,” said Denali CEO Ryan Watts, Ph.D., in a statement
Haurum did not disclose Fcab targets beyond the one already made public—a program focused on transferrin receptors as a target on the blood-brain barrier. Transferrin is a protein in the blood that binds to iron to transport it.
In January, Denali scored $150 million up front from Takeda to work on and sell up to three candidates for neurodegenerative diseases based on its Antibody Transport vehicle platform and Fcabs discovered under the F-star collab. The Bay Area biotech pulled off 2017's biggest IPO, raising $250 million to push drugs being developed for Parkinson's and Alzheimer's diseases through early clinical trials.
Takeda and Denali Therapeutics Collaborate to Develop and Commercialize Therapies for Neurodegenerative Diseases Collaboration includes three named programs for the treatment of Alzheimer’s disease and other neurodegenerative diseases, utilizing Denali’s Antibody Transport Vehicle (ATV) technology to enhance blood-brain barrier (BBB) penetration.
anuary 05, 2018 07:00 AM Eastern Standard Time OSAKA, Japan & SOUTH SAN FRANCISCO, CA--(BUSINESS WIRE)--Takeda Pharmaceutical Company Limited (TSE: 4502) and Denali Therapeutics (NASDAQ: DNLI) today announced that they have entered into a strategic option and collaboration agreement to develop and commercialize up to three specified therapeutic product candidates for neurodegenerative diseases. Each program is directed to a genetically validated target for neurodegenerative disorders, including Alzheimer’s disease and other indications, and incorporates Denali’s ATV platform for increased exposure of biotherapeutic products in the brain.
“This partnership further exemplifies Takeda’s continued commitment to developing genetically validated therapies for neurodegenerative diseases through an enhanced portfolio comprised of new modalities,” said Emiliangelo Ratti, Head of the Neuroscience Therapy Area at Takeda. “We are excited to partner with the Denali team, whose innovative technology is uniquely poised to deliver the next generation of antibody therapeutics for patients.”
“We are impressed with Takeda’s commitment to developing treatments for difficult to treat neurodegenerative diseases and look forward to partnering with them to bring medicines to patients,” said Denali CEO Ryan Watts, Ph.D. “Takeda has a great track record of partnering with biotech firms in addition to unique development expertise and a strong global commercial presence.”
Terms of Collaboration
Under the terms of the agreement, Takeda will make an initial payment to Denali of $150 million through a combination of cash upfront payments and the purchase of Denali equity. In addition, Denali is eligible to receive development and commercial milestone payments, including $90 million in preclinical milestones and opt-in payments.
Denali will be responsible for all development activities and costs prior to IND filing for each of the three programs. Takeda has the option to co-develop and co-commercialize each of the three programs. If Takeda exercises the option, the parties will then jointly conduct clinical development and share all costs equally. Denali will lead early clinical development activities and Takeda will lead late stage clinical development activities. Takeda and Denali will jointly commercialize products in the United States and China, and Takeda will have exclusive commercialization rights in all other markets. The parties will share global profits equally. The agreement will become effective when the requirements of the Hart–Scott–Rodino Antitrust Improvements Act of 1976 have been satisfied.
Our strategy is guided by three overarching principles: • Genetic Pathway Potential : We select our therapeutic targets and disease pathways based on genes that, when mutated, cause, or are major risk factors for, neurodegenerative diseases, which we refer to as degenogenes. • Engineering Brain Delivery : We engineer our product candidates to cross the BBB and act directly in the brain. • Biomarker-Driven Development : We discover, develop and utilize biomarkers to select the right patient population and demonstrate target engagement, pathway engagement and impact on disease progression of our product candidates.
Our total portfolio currently consists of thirteen programs. To prioritize the allocation of our resources, we designate certain programs as core programs and others as seed programs, and we currently have seven core programs and six seed programs. Our most advanced core programs are our LRRK2 inhibitor program to address Parkinson’s disease and our RIPK1 inhibitor program to address Alzheimer’s disease and ALS. The two most advanced product candidates in our LRRK2 program, DNL201 and DNL151, are potent, selective and brain-penetrant small molecule LRRK2 inhibitor product candidates for Parkinson’s disease. DNL201 is currently in a Phase 1 clinical trial in healthy volunteers in the United States, and DNL151 is currently in a Phase 1 clinical trial in healthy volunteers in the Netherlands. The most advanced product candidate in our RIPK1 inhibitor program, DNL747, is a potent, selective and brain-penetrant small molecule RIPK1 inhibitor product candidate for ALS and Alzheimer’s disease is currently in a Phase 1 clinical trial in healthy volunteers in the Netherlands.
We have also developed proprietary drug delivery platform technology designed to deliver large molecules across the BBB. We are currently optimizing and broadening this platform technology. Our ATV and ETV platforms are modular BBB delivery technologies for large molecule therapeutics, including antibodies, enzyme and other proteins. We plan to have multiple product candidates that utilize our ATV or ETV platforms enter clinical development in 2019 and 2020, including molecules targeting aSyn, IDS, TREM2, BACE1 and Tau.
On May 2, 2018, the Company entered into an amendment to the Headquarters Lease described in Note 5, (the “Headquarters Lease Amendment”) to relocate and expand its headquarters to 148,020 rentable square feet in a to-be-constructed building located in South San Francisco, California (the “New Premises”). The Headquarters Lease Amendment has a term of ten years from the commencement date, which is the later of February 1, 2019 or the date that the premises are ready for occupancy. The Company has an option to extend the lease term for a period of ten years by giving the landlord written notice of the election to exercise the option at least nine months, but not more than twelve months, prior to the expiration of the Headquarters Lease Amendment lease term. Under the terms of the Headquarters Lease Amendment, the Company was required to increase the security deposit of $0.5 million described in Note 5 to $1.5 million. The Headquarters Lease Amendment provides for monthly base rent amounts escalating over the term of the lease. In addition, the Headquarters Lease Amendment provides a tenant improvement allowance (“TIA”) of up to $25.9 million, of which $4.4 million, if utilized, would be repaid to the landlord in the form of additional monthly rent with interest applied. Base rent will be approximately $0.4 million per month for the first six months following the commencement of the lease as to the replacement premises, and will increase to approximately $0.7 million per month in month seven and $0.8 million per month after the first year, with 3.5% annual increases thereafter to approximately $12.5 million in the final year of the term. The Company will also be required to pay the Company’s share of operating expenses for the New Premises.
Key operational and financing milestones in the first quarter of 2018 include: • On January 3, 2018, we entered into the Takeda Collaboration Agreement pursuant to which we granted Takeda an option with respect to three of our programs to develop and commercialize, jointly with us, certain biologic products that are enabled by our BBB delivery technology and intended for the treatment of neurodegenerative disorders. Pursuant to this agreement, we received an upfront payment of $40.0 million in February 2018, as well as the first preclinical milestone payment of $5.0 million related to one of our programs. Further, under the associated common stock purchase agreement (the “Stock Purchase Agreement”), we received proceeds of $110.0 million for the sale of 4,214,559 shares of our common stock which were issued on February 23, 2018. • On February 7, 2018, we submitted a CTA for DNL747 to the Netherlands Health Authority, and we initiated a Phase 1 clinical trial of DNL747 in healthy volunteers in the Netherlands in March 2018. • Following the first quarter, in April 2018, one of our pending patent applications directed to the composition of matter of DNL151 issued in the United States
4Q17 SOUTH SAN FRANCISCO, Calif., March 19, 2018 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (NASDAQ:DNLI), a biopharmaceutical company developing a broad portfolio of therapeutic candidates for neurodegenerative diseases, today announced that it has commenced dosing of its small molecule inhibitor of RIPK1 in a Phase 1 clinical trial in healthy volunteers and achieved proof of concept of its large molecule blood-brain barrier delivery platform technology in nonhuman primates. In addition, the Company reported financial results for the fourth quarter and full year ended December 31, 2017 and appointed Peter Klein to the Board of Directors.
"The recent clinical progress with our RIPK1 inhibitor and LRRK2 inhibitor programs, along with achieving proof of concept for our blood-brain barrier delivery platform for biologics in nonhuman primates, are important milestones towards our goal of developing medicines for patients suffering from neurodegenerative diseases," said Ryan Watts, Ph.D., CEO. "Furthermore, we are very excited about initiating our collaboration with Takeda, which has allowed us to expand efforts on our blood-brain barrier delivery technology platform." Fourth Quarter 2017 and Recent Corporate Highlights
Achieved first-in-human dosing in Phase 1 clinical trial of RIPK1 inhibitor program - In March 2018, Denali commenced dosing of its small molecule inhibitor of RIPK1, DNL747, in healthy volunteers in the Netherlands. DNL747 is a potent, selective and brain-penetrant small molecule inhibitor of RIPK1 in development for Alzheimer's disease and ALS. Advanced and expanded LRRK2 inhibitor program - In December 2017, Denali announced that it had achieved robust target engagement in humans with DNL201, a LRRK2 inhibitor, in a Phase 1 clinical trial, and that the FDA removed the partial clinical hold on DNL201. This Phase 1 clinical trial in healthy volunteers for DNL201 is continuing. Denali also announced that it commenced dosing of its second LRRK2 inhibitor, DNL151, in a Phase 1 clinical trial in healthy volunteers in the Netherlands. DNL201 and DNL151 are both potent, selective and brain-penetrant small molecule inhibitors of LRRK2 in development for Parkinson's disease.
Achieved proof of concept of the blood-brain barrier delivery platform technology in nonhuman primates - In January 2018, Denali completed a 28-day study demonstrating sustained brain activity of its proprietary Antibody Transport Vehicle (ATV) technology, as measured by reduction of cerebral spinal fluid amyloid beta in cynomolgus monkeys after dosing of an anti-BACE1 antibody that is enabled by Denali's proprietary ATV technology, compared to a standard anti-BACE1 antibody. These data are consistent with initial 7-day study data previously disclosed and establish preclinical proof of concept for future human studies.
Entered into Option and Collaboration Agreement with Takeda - In January 2018, Denali entered into an Option and Collaboration Agreement with Takeda pursuant to which Denali granted Takeda an option in respect of three named Denali programs to develop and commercialize, jointly with Denali, certain biologic products that are enabled by Denali's blood-brain barrier delivery platform technology and intended for the treatment of neurodegenerative disorders. Denali received $155.0 million of cash associated with this transaction in February 2018, including $110.0 million for Takeda's purchase of 4,214,559 shares of Denali's common stock. Appointed Peter Klein to the Board of Directors - On March 16, 2018, Peter Klein joined the Board of Directors as an independent director. Mr. Klein has 25 years of experience as a senior finance executive. He served as Chief Financial Officer of Microsoft Corporation from November 2009 until May 2013 and spent over 11 years at Microsoft. Most recently, he served as Chief Financial Officer of WME, a global leader in sports and entertainment marketing, from January 2014 until June 2014. Mr. Klein holds a B.A. from Yale University and an M.B.A from University of Washington. He currently serves on the board of directors of two publicly traded companies: Apptio Inc. and F5 Networks, Inc. Raised net proceeds of $294.2 million during the fourth quarter of 2017 through the sale of convertible preferred stock and a subsequent initial public offering and listing on the Nasdaq Global Select Market. Fourth Quarter and Full Year 2017 Financial Results For the fourth quarter of 2017, Denali reported a net loss of $22.9 million, compared with a net loss for the fourth quarter of 2016 of $19.4 million. For the year ended December 31, 2017, net loss was $88.2 million, compared with a net loss for the same period in 2016 of $86.7 million.
ATV is well differentiated from other BBB approaches • Integrates BBB target binding site into IgG format • No need for unnatural linkers or appended sequences • Antibody-like stability and pharmacokinetic properties • Bivalent or bispecific target binding enabled • Initial in vivo proof of concept data in hu/ms TfR KI mouse and monkey
Genentech On June 17, 2016, we entered into an Exclusive License Agreement with Genentech. The agreement gives us access to Genentech’s preclinical stage LRRK2 small molecule program, which can be used to enhance and further progress our in-house LRRK2 program for Parkinson’s disease. As consideration, we paid an upfront fee of $8.5 million and a technology transfer fee of $1.5 million, both of which are included in research and development expense for the year ended December 31, 2016 as there is no alternative future use of the rights acquired in other research and development projects. We may owe Genentech milestone payments upon the achievement of certain development, regulatory, and commercial milestones, up to a maximum of $315.0 million in the aggregate, as well as royalties on net sales of licensed products ranging from low to high single-digit percentages, with the exact royalty rate dependent on various factors, including (i) whether the compound incorporated in the relevant licensed product is a Genentech-provided compound or a compound acquired or developed by us, (ii) the date a compound was first discovered, derived or optimized by us, (iii) the existence of patent rights covering the relevant licensed product in the relevant country, (iv) the existence of orphan drug exclusivity covering a licensed product that is a Genentech-provided compound and (v) the level of annual net sales of the relevant licensed product. We also have the right to credit a certain amount of third-party royalty and milestone payments against royalty and milestone payments owed to Genentech, up to a maximum reduction of fifty percent. The first clinical milestone of $2.5 million became due upon first patient dosing in the Phase 1 clinical trial for DNL201. The full amount was recognized in research and development expense in the nine months ended September 30, 2017. Unless earlier terminated, the agreement with Genentech will continue in effect until all of our royalty and milestone payment obligations to Genentech expire. Following expiration of the agreement, we will retain the licenses under the intellectual property Genentech licensed to us on a non-exclusive, royalty-free basis.
As of February 28, 2018, our owned and licensed patent portfolio includes over 650 patents and patent applications, including over 20 licensed U.S. issued patents, over 15 licensed U.S. pending patent applications, 2 owned U.S. issued patents, and over 30 owned U.S. pending patent applications, covering certain aspects of our proprietary technology, our product candidates, and related inventions and improvements. The patent portfolio also includes over 200 licensed patents issued in jurisdictions outside of the United States, over 85 licensed patent applications pending in jurisdictions outside of the United States, and over 10 owned patent applications pending in jurisdictions outside of the United States that, in many cases, are counterparts to the foregoing U.S. patents and patent applications. For our product candidates and our BBB platform technology, we generally pursue or in-license patent protection covering compositions of matter, methods of use and manufacture. For example, we own patent applications in the United States and internationally that are directed to the composition of matter of certain antibodies and small molecule product candidates that we intend to develop or are developing, as well as the Fc domain portion of our BBB platform technology. For our BBB platform technology and ATV/ETV programs, we license multiple patent families from F-star, the earliest issued patents of which are expected to expire in 2026, not including any patent term adjustments and any patent term extensions. Furthermore, we own pending patent applications directed to the composition and sequences of our TfR-binding ATVs and other BBB platform technology. For our ATV:BACE1/Tau program, we license patents from VIB, which are expected to expire in 2030, not including any patent term adjustments and any patent term extensions. Furthermore, we own patent applications directed to our ATV:BACE1/Tau, ATV:aSyn, ATV:TREM2, and ETV:IDS programs. For our LRRK2 program, we license multiple patent families from Genentech directed to, among other things, our LRRK2 program, including DNL201, DNL151 and other related compounds, which are expected to expire in 2031, not including any patent term adjustments and any patent term extensions; and we own pending patent applications directed to the composition of matter of DNL151. For our RIPK1 program, we own two issued U.S. patents, which are expected to expire in 2037, not including any patent term adjustments and any patent term extensions and pending patent applications, which are directed to the composition of matter of DNL747 as well as other RIPK1 inhibitor compounds
Under: Been on the sidelines for a bit holding (building) cash. Now that "BIGLEY" has rolled out the tax plan its time to jump in.
Dec 21, 2017 19:06:02 GMT -6
martyc: Looks like you are buying Msft again!
Dec 15, 2017 11:23:29 GMT -6
martyc: The news that Trump called Rupert to congratulate him sure seems to indicate that this is heading to approval
Dec 15, 2017 11:22:23 GMT -6
Under: DIS finally getting some traction.?
Dec 14, 2017 17:08:45 GMT -6
martyc: I took an entry level position in DIS. Will add eventually to overweight when it becomes clearer that the deal will go thru. Can't believe how well positioned they will be. 60% Hulu. 20% of content watched on NFLX they can pull. More in thread
Dec 14, 2017 11:05:16 GMT -6
Under: Great posts on $DIS
Dec 13, 2017 17:50:49 GMT -6
Under: $ROKU Citron on a war path.
Nov 28, 2017 15:11:20 GMT -6
Under: $HAS takeover bid for $MAT?
Nov 10, 2017 16:16:07 GMT -6
martyc: Not looking like the market will provide any discounted opp for SGMO. Call was just too professional and all signs indicate they are on a great path for commercialization. Happy with core but wish I had some trading shs
Nov 10, 2017 9:04:05 GMT -6
martyc: For anyone looking to find an entry point into SGMO, I'm almost hoping is sells off in next few days so I can add more. They are really clicking but the fact they haven't signed new deals might cause some to exit. Watching as I have room for trading shs
Nov 9, 2017 18:28:09 GMT -6
martyc: Been an interesting ride so far. I figured the Bears would be about this good but hoped the O wouldn't look so lame. Another building yr but still possible to get to 8-8 IMO
Nov 9, 2017 18:26:08 GMT -6
Under: whats up with your Bears this year Marty?
Nov 9, 2017 17:35:25 GMT -6
martyc: Hope you were long ROKU. I wanted to see Q first so missed out
Nov 9, 2017 7:08:53 GMT -6