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• Due to the significant resources required for the development of our programs, and depending on our ability to access capital, we must prioritize development of certain product candidates.
−Removed: • A pandemic, epidemic, or outbreak of an infectious disease, or the perception of its effects, may materially and adversely affect our business, operations, and financial condition.
Risks Related to the Discovery, Development and Commercialization of Our Product Candidates
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We are in the clinical stages of drug development and have a limited operating history and no products approved for commercial sale, which may make it difficult to evaluate our business and predict our future success and viability.
−Removed: We are a clinical-stage biopharmaceutical company with a limited operating history, focused on developing therapeutics for neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and ALS, and lysosomal storage diseases , including Hunter syndrome and Sanfilippo syndrome.
+Added: We are a clinical-stage biopharmaceutical company with a limited operating history, focused on developing therapeutics for neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, and lysosomal storage diseases , including Hunter syndrome and Sanfilippo syndrome.
We commenced operations in May 2015 , have no products approved for commercial sale, and have not generated any revenue from product sales.
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We have incurred significant net losses since our inception.
−Removed: Our net losses were $133.0 million and $101.8 million for the three months ended March 31, 2025, and 2024, respectively.
−Removed: As of March 31, 2025 , we had an accumulated deficit of $1.67 billion .
+Added: Our net losses were $124.1 million and $257.1 million for the three and six months ended June 30, 2025, respectively, and net losses of $99.0 million and $200.8 million for the three and six months ended June 30, 2024, respectively.
+Added: As of June 30, 2025 , we had an accumulated deficit of $1.80 billion .
We have invested significant financial resources in research and development activities, including for our preclinical and clinical product candidates and our TV platform.
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• attract, hire, and retain qualified personnel and incur increased stock-based compensation, especially in light of a competitive compensation environment;
−Removed: • provide additional internal infrastructure to support our continued research and development operations and any planned commercialization efforts in the future;
+Added: • provide additional internal infrastructure to support our continued research and development operations and commercialization efforts;
• implement additional internal systems and infrastructure related to cybersecurity;
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Developing our product candidates is expensive, and we expect to continue to spend substa ntial amounts as we fund our early-stage research projects and advance our programs through preclinical and clinical development.
−Removed: As of March 31, 2025, we had $1.05 billion in cash, cash equivalents and marketable securities.
+Added: As of June 30, 2025, we had $977.4 million in cash, cash equivalents and marketable securities.
We believe that our existing cash, cash equivalents and marketable securities will be sufficient to fund our projected operations through at least the next twelve months.
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Further, we canno t be certain that any of our product candidates will be successful in clinical trials.
−Removed: For instance, in August 2023, together with our collaboration partner Takeda, we discontinued development of TAK-920/DNL919 (ATV:TREM2) in Alzheimer’s disease, based on data from the Phase 1 study and the rapidly evolving treatment landscape, and, in January 2025, we announced that the Phase 2/3 HEALEY ALS Platform Trial evaluating DNL343 for ALS did not meet primary and key secondary endpoints.
+Added: For instance, in January 2025, we announced that the Phase 2/3 HEALEY ALS Platform Trial evaluating DNL343 for ALS did not meet primary and key secondary endpoints.
We may in the future advance product candidates into clinical trials and terminate such trials prior to their completion.
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Collectively, efforts by biopharmaceutical companies in the fields of neurodegenerative and lysosomal storage diseases have seen limited success in drug development.
−Removed: There are few effective therapeutic options available for patients with neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and ALS, and lysosomal storage diseases , such as Hunter syndrome and Sanfilippo syndrome.
+Added: There are few effective therapeutic options available for patients with neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, and lysosomal storage diseases , such as Hunter syndrome and Sanfilippo syndrome.
Our future success is highly dependent on the successful development of our TV platform and our product candidates for treating neurodegenerative and lysosomal storage diseases .
Developing and, if approved, commercializing our product candidates for treatment of neurodegenerative and lysosomal storage diseases subjects us to a number of challenges, including engineering product candidates to cross the BBB to enable optimal concentration of the therapeutic in the brain and obtaining regulatory approval from the FDA and other regulatory authorities who have only a limited set of precedents to rely on.
−Removed: Our approach to the treatment of neurodegenerative and lysosomal storage diseases aims to identify and select targets with a genetic link to neurodegenerative and lysosomal storage diseases , as applicable, identify and develop molecules that engage the intended target, identify and develop biomarkers, which are biological molecules found in blood, other bodily fluids or tissues that are signs of a normal or abnormal process or of a condition or disease, to select the right patient population and demonstrate target engagement, pathway engagement and impact on disease progression of our molecules, and engineer our molecules to cross the BBB and act directly in the brain.
+Added: Our approach to the treatment of neurodegenerative and lysosomal storage diseases aims to identify and select targets with a genetic link to neurodegenerative and lysosomal storage diseases;
+Added: identify and develop molecules that engage the intended target;
+Added: identify and develop biomarkers, which are biological molecules found in blood, other bodily fluids, or tissues that are signs of a normal or abnormal process or of a condition or disease, to select the right patient population and demonstrate target engagement, pathway engagement, and impact on disease progression of our molecules;
+Added: and engineer our molecules to cross the BBB and act directly in the brain.
This strategy may not prove to be successful.
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Most product candidates that begin clinical trials are never approved by regulatory authorities for commercialization.
−Removed: We cannot be certain that our current clinical trials or any other future clinical trials will be successful.
+Added: We cannot be certain that our current clinical trials or any future clinical trials will be successful.
Additionally, any safety concerns observed in any one of our clinical trials in our targeted indications could limit the prospects for regulatory approval of our product candidates in those and other indications, which could have a material adverse effect on our business, financial condition, results of operations and growth prospects.
Even if such clinical trials are successfully completed, we cannot guarantee that the FDA will approve the product candidates for the proposed indications, and more trials could be required before we submit our product candidates for approval.
−Removed: For instance, although we have submitted a biologics license application ("BLA") for accelerated approval of DNL310, we expect the FDA will require us to conduct a confirmatory trial post any approval.
−Removed: To the extent that the results of the trials are not satisfactory to the FDA or foreign regulatory authorities for support of a marketing application, we may be required to expend significant resources, which may not be available to us, or to conduct additional trials in support of potential approval of our product candidates.
+Added: For instance, although the FDA has accepted our biologics license application ("BLA") for accelerated approval of DNL310, we expect the FDA will require us to conduct a confirmatory trial post any approval.
+Added: To the extent that the results of the trials are not satisfactory to the FDA or foreign regulatory authorities for support of a marketing application, we may be required to expend significant resources, which may not be available to us, to conduct additional trials in support of potential approval of our product candidates.
Even if regulatory approval is secured for any of our product candidates, the terms of such approval, such as requiring us to narrow our indications to a smaller subset, may also limit its commercial potential.
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Our competitors, either alone or with collaborative partners, may succeed in developing, acquiring, or licensing on an exclusive basis drug or biologic products that are more effective, safer, more easily commercialized, or less costly than our product candidates or may develop proprietary technologies or secure patent protection that we may need for the development of our technologies and products.
−Removed: A number of large pharmaceutical and biotechnology companies are developing products for the treatment of the neurodegenerative and lysosomal storage disease indications for which we have research programs, including Alzheimer’s disease, Parkinson’s disease, Hunter syndrome, Sanfilippo syndrome, and ALS.
+Added: A number of large pharmaceutical and biotechnology companies are developing products for the treatment of the neurodegenerative and lysosomal storage disease indications for which we have research programs, including Alzheimer’s disease, Parkinson’s disease, Hunter syndrome, and Sanfilippo syndrome.
Companies that we are aware are developing therapeutics in the neurodegenerative and lysosomal storage disease areas include companies with significant financial resources.
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Even if we are successful in achieving regulatory approval to commercialize a product candidate faster than our competitors, our large molecule product candidates may face competition from biosimilar products.
−Removed: In the United States, our large molecule product candidates, including DNL310, are regulated by the FDA as biologic products and we intend to seek approval for these product candidates pursuant to the biologics license application ("BLA"), pathway.
+Added: In the United States, our large molecule product candidates, including DNL310, are regulated by the FDA as biologic products.
+Added: We have sought approval for DNL310 pursuant to the biologics license application ("BLA") pathway and may do so for other large molecule product candidates in our pipeline.
The Biologics Price Competition and Innovation Act of 2009 (the "BPCIA"), created an abbreviated pathway for the approval of biosimilar and interchangeable biologic products.
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Moreover, regulatory authorities may fail to approve companion diagnostics that we contemplate using with our therapeutic product candidates.
−Removed: We have not submitted for, or obtained regulatory approval for any product candidate, and it is possible that none of our existing product candidates or any product candidates we may seek to develop in the future will ever obtain regulatory approval.
+Added: We have not obtained regulatory approval for any product candidate, and it is possible that none of our existing product candidates or any product candidates we may seek to develop in the future will ever obtain regulatory approval.
Changes to the leadership and staffing at federal agencies may impact our clinical development and timelines.
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We could also be asked to conduct post-marketing clinical trials to verify the safety and efficacy of our non-biologic products or safety, purity, and potency for our biologic products, in general or in specific patient subsets.
−Removed: We plan to seek accelerated approval of DNL310.
+Added: We are seeking accelerated approval of DNL310.
If successful, we expect the FDA will require us to conduct a confirmatory study to verify the predicted clinical benefit and safety profile.
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Chamber of Commerce, and the Pharmaceutical Research and Manufacturers of America, have initiated lawsuits against the federal government asserting that the price negotiation provisions of the Inflation Reduction Act ("IRA") are unconstitutional.
−Removed: The impact of these judicial changes, future litigation brought in view of
−Removed: the Supreme Court’s overrule of the Chevron doctrine, legislative, executive, and administrative actions and any future healthcare measures and agency rules implemented by the government on us and the pharmaceutical industry as a whole is unclear.
+Added: The impact of these judicial changes, future litigation brought in view of the Supreme Court’s overrule of the Chevron doctrine, legislative, executive, and administrative actions and any future healthcare measures and agency rules implemented by the government on us and the pharmaceutical industry as a whole is unclear.
At the state level, a number of states are considering or have recently enacted state drug price transparency and reporting laws that could substantially increase our compliance burdens and expose us to greater liability under such state laws once we begin commercialization after obtaining regulatory approval for any of our products.
Since its enactment, there have been executive, judicial and congressional challenges to certain aspects of the ACA and IRA.
−Removed: It is unclear how future litigation or healthcare measures promulgated by the Biden administration will impact our business, financial condition, and results of operations.
+Added: It is unclear how future litigation or healthcare measures will impact our business, financial condition, and results of operations.
Complying with any new legislation or changes in healthcare regulation could be time-intensive and expensive, resulting in material adverse effect on our business.
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Additionally, the U.S.
−Removed: Department of Justice recently issued a final rule that takes effect in April 2025 and places limitations, and in some cases prohibitions, on certain transfers of sensitive personal data to business partners located in China or with other specified links to China (and other designated countries).
+Added: Department of Justice recently implemented a final rule that places limitations, and in some cases prohibitions, on certain transfers of sensitive personal data to business partners located in China or with other specified links to China (and other designated countries).
The GDPR, UK GDPR, CCPA, CPRA, and many other federal, state, and foreign laws and regulations relating to privacy and data protection are still being tested in courts, and they are subject to new and differing interpretations by courts and regulatory officials.
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We seek to protect our proprietary position by in-licensing intellectual property and filing patent applications in the United States and abroad relating to our TV platform, programs and product candidates, as well as other technologies that are important to our business.
−Removed: Given that the development of our technology and product candidates is at an early stage, our intellectual property portfolio with respect to certain aspects of our technology and product candidates is also at an early stage.
+Added: Our portfolio includes technology and product candidates that are in the early stages of development, and the corresponding intellectual property is also at an early stage.
In addition, we cannot be certain that any patents we own or in-license in the United States adequately cover the Fc domain portion of our TV platform that binds to transferrin receptor, or adequately cover the antibodies, enzymes or proteins being developed in our TV-enabled programs.
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Furthermore, European applications have the option, upon grant of a patent, of becoming a Unitary Patent and therefore subject to UPC.
−Removed: This will be a significant change in European patent practice.
−Removed: As the UPC is a new court system, there is no precedent for the court, increasing the uncertainty.
+Added: This is a significant change in European patent practice.
+Added: As the UPC is a new court system, there is limited precedent for the court, increasing the uncertainty.
Proceedings to enforce our intellectual property and proprietary rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly, could put our patent applications at risk of not issuing, and could provoke third parties to assert claims against us.
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The loss of the services provided by any of our executive officers, other key employees, and other scientific and medical advisors, and our inability to find suitable replacements, could result in delays in the development of our product candidates and harm our business.
−Removed: We primarily conduct our operations at our facility in South San Francisco, a region that is headquarters to many other biopharmaceutical companies and many academic and research institutions.
+Added: The majority of our operations are conducted at our facility in South San Francisco, a region that is headquarters to many other biopharmaceutical companies and many academic and research institutions.
Competition for skilled personnel is intense and the turnover rate can be high, which may limit our ability to hire and retain highly qualified personnel on acceptable terms or at all.
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We will need to grow the size and capabilities of our organization, and we may experience difficulties in managing this growth.
−Removed: As of March 31, 2025, we had approximately 443 emplo yees, all of whom were full-time.
+Added: As of June 30, 2025, we had approximately 486 emplo yees, all of whom were full-time.
As our development plans and strategies develop, we must add a significant number of additional managerial, operational, financial, and other personnel.
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Our directors, executive officers, holders of more than 5% of our outstanding stock, and their respective affiliates beneficially own a significant percentage of our outstanding common stock.
−Removed: As a result, these stockholders, if they act together, may significantly influence all matters requiring stockholder approval, including the election of directors and approval of significant corporate transactions.
−Removed: In addition, pursuant to a nominating agreement between us and Baker Brothers Life Sciences L.P.
+Added: As a result, these stockholders, if they act together, may significantly influence all matters requiring stockholder approval, including the approval of significant corporate transactions and the election of directors, as with the recent board nomination and election of a director designated by Baker Brothers Life Sciences L.P.
and 667, L.P.
−Removed: ("Baker Brothers"), if Baker Brothers were to beneficially own at least 10% of our common stock, we would have the obligation to support the nomination of, and to cause our board of directors to include in the slate of nominees recommended to our stockholders for election, one individual designated by Baker Brothers, subject to customary conditions and exceptions.
−Removed: This concentration of ownership may result in such holders exerting influence over us and may have the effect of delaying or preventing a change in control of our company that our other stockholders may believe is in their best interests.
+Added: ("Baker Brothers") pursuant to a nominating agreement.
+Added: Any concentration of ownership may result in such holders exerting influence over us and may have the effect of delaying or preventing a change in control of our company that our other stockholders may believe is in their best interests.
This in turn could have a material adverse effect on our stock price and may prevent attempts by our stockholders to replace or remove the board of directors or management.
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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.