UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
Form
CURRENT REPORT
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| Item 2.02 | Results of Operations and Financial Condition. |
On May 12, 2022, Wave Life Sciences Ltd. (the “Company”) announced its financial results for the quarter ended March 31, 2022. The full text of the press release issued in connection with the announcement is furnished as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated by reference herein.
| Item 7.01 | Regulation FD Disclosure. |
From time to time, the Company presents and/or distributes slides and presentations to the investment community to provide updates and summaries of its business. On May 12, 2022, the Company updated its corporate presentation, which is available on the “For Investors & Media” section of the Company’s website at http://ir.wavelifesciences.com/. This presentation is also furnished as Exhibit 99.2 to this Current Report on Form 8-K.
The information in these Items 2.02 and 7.01 are being furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that Section, nor shall they be deemed incorporated by reference into any registration statement or other filing under the Securities Act of 1933, as amended, or the Exchange Act, except as shall be expressly set forth by specific reference in such filing.
| Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits
The following exhibits relating to Items 2.02 and 7.01 are furnished and not filed:
| Exhibit No. | Description | |
| 99.1 | Press Release issued by Wave Life Sciences Ltd. dated May 12, 2022 | |
| 99.2 | Corporate Presentation of Wave Life Sciences Ltd. dated May 12, 2022 | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| WAVE LIFE SCIENCES LTD. | ||
| By: |
/s/ Paul B. Bolno, M.D. | |
| Paul B. Bolno, M.D. | ||
| President and Chief Executive Officer | ||
Date: May 12, 2022
Exhibit 99.1
Wave Life Sciences Reports First Quarter 2022 Financial Results and Provides Business Update
Delivered first clinical data demonstrating target engagement and translation of PN chemistry’s impact in clinic;
Adapting ongoing Phase 1b/2a FOCUS-C9 clinical trial to optimize dose level and frequency, with additional single and
multidose data expected throughout 2022
Clinical data also expected in 2022 from Huntington’s disease (WVE-003) and Duchenne muscular dystrophy (WVE-N531)
trials
Robust preclinical datasets for first-in-class AATD program demonstrate restoration of levels of AAT relevant for
potential lung protection and reduction of liver-damaging aggregates with GalNAc AIMers; IND enabling toxicology
studies for lead AATD candidate on-track to initiate in 3Q 2022
Wave to host investor conference call and webcast at 8:30 a.m. ET today
CAMBRIDGE, Mass., May 12, 2022 – Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases, today announced financial results for the first quarter ended March 31, 2022 and provided a business update.
“Thus far in 2022, Wave has achieved several important milestones, with the highlight being our first clinical data demonstrating successful target engagement with WVE-004 in the ongoing FOCUS-C9 clinical trial for C9-ALS and C9-FTD. We observed potent and durable reductions of the poly(GP) biomarker with low single doses of WVE-004, demonstrating that our preclinical data for PN-containing oligonucleotides are beginning to translate in the clinic,” said Paul Bolno, MD, MBA, President and Chief Executive Officer of Wave Life Sciences. “These initial results are compelling and reinforce the potential of our unique oligonucleotide platform and our expectation to see the advantages of PN chemistry manifest in our other pipeline programs. We also continue to rapidly advance our WVE-003 program for HD and WVE-N531 program for DMD towards initial data updates later this year. We are also pleased with the recognition we are receiving with our endogenous RNA editing modality, which is being highlighted through scientific presentations and our recent Nature Biotechnology publication. Alpha-1 antitrypsin deficiency (AATD) is uniquely suited for an RNA editing therapeutic, and our AATD program is rapidly advancing towards clinical development with IND enabling studies on track to initiate in the third quarter of this year.”
Recent Pipeline and Business Highlights
Announced first clinical data from ongoing FOCUS-C9 trial of WVE-004 for C9-ALS and C9-FTD demonstrating potent and durable target engagement with low, single doses
| • | In April 2022, Wave announced a positive update to its ongoing FOCUS-C9 trial of WVE-004 (stereopure, PN-modified silencing oligonucleotide) for C9orf72-associated amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD). The update was driven by the observation of potent and durable reductions of poly(GP) dipeptide repeat proteins in cerebrospinal fluid (CSF), a C9-ALS/C9-FTD disease biomarker that, when reduced in CSF, indicates WVE-004’s engagement of target in the brain and spinal cord. Based on the poly(GP) reduction data, the observation period for single dose cohorts is being extended and additional |
| patients are being enrolled into the trial to further characterize depth of knockdown, durability and longer-term safety profile. Wave plans to share this recently announced clinical data in an oral presentation at the upcoming European Network to Cure ALS (ENCALS) Meeting in Edinburgh, Scotland, which is taking place June 1 – 3, 2022. |
| • | FOCUS-C9 (NCT04931862) is an adaptive trial that was designed to rapidly optimize dose level and frequency based on early indicators of target engagement. WVE-004 is designed to selectively target transcript variants containing a hexanucleotide repeat expansion (G4C2) associated with the C9orf72 gene for the treatment of C9-ALS and C9-FTD, thereby reducing pathological mRNA products and toxic DPR proteins, including poly(GP). Planning is underway to initiate an open-label extension (OLE) clinical trial in mid-2022. |
Continued to advance clinical trials evaluating WVE-003 targeting SNP3 for Huntington’s disease (HD) and WVE-N531 for Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping
| • | WVE-003 for HD (PN-modified silencing oligonucleotide) is being evaluated in the ongoing, adaptive, double-blind Phase 1b/2a SELECT-HD (NCT05032196) clinical trial. WVE-003 is designed to selectively target the mutant allele of the huntingtin (mHTT) gene, while leaving the wild-type (healthy) HTT (wtHTT) protein relatively intact. |
| • | WVE-N531 for DMD (PN-modified splicing oligonucleotide) is being evaluated in an open-label, intra-patient dose escalation (NCT04906460) clinical trial. Dose escalation is ongoing and being guided by tolerability and plasma PK, with possible cohort expansion informed by an assessment of drug distribution in muscle and biomarkers, including dystrophin, following multiple doses of WVE-N531. |
Presented preclinical AIMer data for AATD program supporting the potential for a novel, first-in-class, subcutaneous therapeutic to address both lung and liver manifestations of disease
| • | In March 2022, preclinical data for Wave’s Alpha-1 antitrypsin deficiency (AATD) AIMer program demonstrating restoration of functional AAT protein and reduction of liver aggregates in a transgenic mouse model was shared in a Featured Session at the 7th Annual Oligonucleotide & Precision Therapeutics (OPT) Congress. At 19 weeks, GalNAc-conjugated SERPINA1 AIMers resulted in approximately 60% RNA editing of SERPINA1 transcript and circulating serum AAT levels (18.5 uM) in AIMer administered mice that were approximately 5-fold greater than PBS-administered controls. |
| • | Today, May 12, 2022, at the TIDES USA: Oligonucleotide & Peptide Therapeutics Conference, Wave is presenting additional preclinical data that confirmed restored AAT protein in serum was functional at week 19, as measured by a 3-fold increase in neutrophil elastase inhibition over placebo control. A histological analysis indicated reduction of liver aggregates in a transgenic mouse model at 19 weeks with AIMers. Wave will also share these data in an oral presentation at the American Society of Gene and Cell Therapy (ASGCT) 25th Annual Meeting taking place May 16 – 19, 2022 in Washington, D.C. |
Scientific publications highlight breadth and potential of Wave’s therapeutic oligonucleotide platform, including novel PN-chemistry and RNA editing modality
| • | In March 2022, preclinical proof-of-concept data for Wave’s novel ADAR-mediated RNA base editing modality was published in the journal Nature Biotechnology – the first scientific publication to report that RNA base editing in NHPs can be achieved with a simplified oligonucleotide approach. Data reported include an in vivo study where Wave’s GalNAc-conjugated A-to-I(G) RNA base editing oligonucleotides (“AIMers”) yielded up to 50% editing of ACTB (Beta-actin) transcript in the liver of non-human primates (NHPs), with editing levels persisting as high as 40% for more than one month. |
| • | In February 2022, two papers were published in the journal Nucleic Acids Research (NAR) that reported a multitude of preclinical in vitro and in vivo studies demonstrating the incorporation of PN backbone chemistry modifications (PN chemistry) in stereopure silencing oligonucleotides (publication link) and stereopure splicing oligonucleotides (publication link) significantly improves potency, distribution, and durability of effect. |
| • | Wave has published a total of eight peer-reviewed papers thus far in 2022. |
Key Anticipated 2022 Milestones
WVE-004 for C9-ALS and C9-FTD:
| • | Additional single and multidose clinical data for WVE-004 expected throughout 2022. Wave expects to use these data to optimize WVE-004 dose level and frequency, as well as to enable discussions with regulatory authorities regarding the next phase of development later in 2022. |
| • | Planning underway to initiate an open-label extension (OLE) clinical trial in mid-2022. |
WVE-003 for HD:
| • | Clinical data expected in 2022 for WVE-003 to provide further insight into the clinical effects of PN chemistry and enable decision-making for this program. |
WVE-N531 for DMD:
| • | Clinical data, including muscle biopsies, expected in 2022 for WVE-N531 to provide further insight into the clinical effects of PN chemistry and enable decision-making for this program. |
AIMer GalNAc-conjugated program for AATD:
| • | Wave expects to select an AATD AIMer development candidate and initiate IND-enabling toxicology studies in the third quarter of 2022. |
First Quarter 2022 Financial Results and Financial Guidance
Wave reported a net loss of $37.8 million in the first quarter of 2022, as compared to $42.5 million in the same period in 2021.
Wave recorded revenue of $1.8 million for the first quarter of 2022, primarily under the Takeda Collaboration. Wave did not record any revenue under the Takeda Collaboration in the first quarter of 2021.
Research and development expenses were $27.5 million in the first quarter of 2022 as compared to $33.4 million in the same period in 2021. The decrease in research and development expenses in the first quarter was primarily due to decreased external expenses related to our previously disclosed discontinued PRECISION-HD programs, partially offset by increased internal and external expenses related to PRISM, including ADAR editing, and other ongoing programs.
General and administrative expenses were $12.4 million in the first quarter of 2022 as compared to $10.1 million in the same period in 2021. The increase in general and administrative expenses in the first quarter of 2022 was primarily due to increases in compensation-related expenses, as well as increases in professional services expenses and other general and administrative operating expenses.
As of March 31, 2022, Wave had $111.7 million in cash, cash equivalents and short-term investments. As of December 31, 2021, Wave had $150.6 million in cash and cash equivalents. This decrease was mainly due to Wave’s year-to-date net loss of $37.8 million.
Wave expects that its existing cash, cash equivalents and short-term investments will enable the company to fund its operating and capital expenditure requirements into the second quarter of 2023.
Investor Conference Call and Webcast
Wave management will host an investor conference call today at 8:30 a.m. ET to discuss the company’s first quarter 2022 financial results and provide a business update. The conference call may be accessed by dialing (866) 220-8068 (domestic) or (470) 495-9153 (international) and entering conference ID: 092347. The live webcast may be accessed from the Investor Relations section of the Wave Life Sciences corporate website at ir.wavelifesciences.com. Following the webcast, a replay will be available on the website.
About the FOCUS-C9 Clinical Trial
The FOCUS-C9 trial is an ongoing, global, multicenter, randomized, double-blind, placebo-controlled Phase 1b/2a clinical trial to assess the safety and tolerability of single- and multiple-ascending intrathecal doses of WVE-004 for people with C9-ALS and/or C9-FTD. Additional objectives include measurement of poly(GP) DPR proteins in the cerebrospinal fluid (CSF), plasma and CSF pharmacokinetics (PK), and exploratory biomarkers and clinical outcomes. The FOCUS-C9 trial is designed to be adaptive, with dose escalation and dosing frequency being guided by an independent committee.
In an initial data analysis, reductions in poly(GP) were observed across all active treatment groups (10 mg, n=2 patients; 30 mg, n=4 patients; 60 mg, n=3 patients), reaching statistical significance versus placebo (n=3 patients) after single 30 mg doses, with a 34% reduction in poly(GP) at day 85 (p=0.011). At the time of analysis, none of the patients dosed with 60 mg had reached day 85. As the poly(GP) reduction in the 30 mg single dose cohort does not appear to have plateaued, Wave will extend the observation period from approximately three months (85 days) to approximately six months to identify the maximum reduction of poly(GP) and duration of effect of low single doses. Based on the durability and potency observed in the 30 mg cohort, FOCUS-C9 has been adapted to include additional patients receiving 20 mg and 30 mg single doses of WVE-004. Adverse events (AEs) were balanced across treatment groups, including placebo, and were mostly mild to moderate in intensity. Four patients (including one on placebo) experienced severe and/or serious adverse events; three were reported by the investigators to be related to ALS or administration, and one was reported by the investigator to be related to study drug. There were no treatment-associated elevations in CSF white blood cell counts or protein and no other notable laboratory abnormalities were observed.
Support for FOCUS-C9 is provided by the Alzheimer’s Drug Discovery Foundation.
About Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which the progressive degeneration of motor neurons in the brain and spinal cord leads to the inability to initiate or control muscle movement. People with ALS may lose the ability to speak, eat, move and breathe. ALS affects as many as 20,000 people in the United States.
Frontotemporal dementia (FTD) is a fatal neurodegenerative disease in which progressive nerve cell loss in the brain’s frontal lobes and temporal lobes leads to personality and behavioral changes, as well as the gradual impairment of language skills. It is the second most common form of early-onset dementia after Alzheimer’s disease in people under the age of 65. FTD affects as many as 70,000 people in the United States.
A hexanucleotide repeat expansion (G4C2) is the most common known genetic cause of the sporadic and inherited forms of ALS and FTD. The expansion leads to production of modified sense and antisense transcripts that can form nuclear RNA foci and encode dipeptide protein repeats (DPRs), which are believed to drive disease pathology. Additionally, the G4C2 expansion can decrease expression of C9orf72 protein, affecting regulation of neuronal function and the immune system.
In the United States, mutations of the C9orf72 gene are present in approximately 40% of familial ALS cases and ~8-10% of sporadic ALS cases. In FTD, the mutations appear in 38% of familial cases and 6% of sporadic cases.
About Huntington’s Disease
Huntington’s disease (HD) is a debilitating and ultimately fatal autosomal dominant neurological disorder, characterized by cognitive decline, psychiatric illness, and chorea. HD causes nerve cells in the brain to deteriorate over time, affecting thinking ability, emotions, and movement. HD is caused by an expanded cytosine-adenine-guanine (CAG) triplet repeat in the huntingtin (HTT) gene that results in production of mutant HTT (mHTT) protein. Accumulation of mHTT causes progressive loss of neurons in the brain. Wild-type, or healthy, HTT (wtHTT) protein is critical for neuronal function and suppression may have detrimental long-term consequences. Approximately 30,000 people in the United States have symptomatic HD and more than 200,000 others are at risk for developing the disease. There are currently no approved disease-modifying therapies available.
About Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic neuromuscular disorder caused predominantly by out-of-frame deletions in the dystrophin gene, resulting in absent or defective dystrophin protein. Dystrophin protein is needed for normal muscle maintenance and operation. Because of the genetic mutations in DMD, the body cannot produce functional dystrophin, which results in progressive and irreversible loss of muscle function, including the heart
and lungs. Worldwide, DMD affects approximately one in 5,000 newborn boys. Approximately 8%-10% of DMD patients have mutations amenable to treatment with an exon 53 skipping therapy. Exon skipping aims to address the underlying cause of DMD by promoting the production of dystrophin protein to stabilize or slow disease progression
About PRISM™
PRISM is Wave Life Sciences’ proprietary discovery and drug development platform that enables genetically defined diseases to be targeted with stereopure oligonucleotides across multiple therapeutic modalities, including silencing, splicing and editing. PRISM combines the company’s unique ability to construct stereopure oligonucleotides with a deep understanding of how the interplay among oligonucleotide sequence, chemistry and backbone stereochemistry impacts key pharmacological properties. By exploring these interactions through iterative analysis of in vitro and in vivo outcomes and machine learning-driven predictive modeling, the company continues to define design principles that are deployed across programs to rapidly develop and manufacture clinical candidates that meet pre-defined product profiles.
About Wave Life Sciences
Wave Life Sciences (Nasdaq: WVE) is a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases. Wave aspires to develop best-in-class medicines across multiple therapeutic modalities using PRISM, the company’s proprietary discovery and drug development platform that enables the precise design, optimization, and production of stereopure oligonucleotides. Driven by a resolute sense of urgency, the Wave team is targeting a broad range of genetically defined diseases so that patients and families may realize a brighter future. To find out more, please visit www.wavelifesciences.com and follow Wave on Twitter @WaveLifeSci.
Forward-Looking Statements
This press release contains forward-looking statements concerning our goals, beliefs, expectations, strategies, objectives and plans, and other statements that are not necessarily based on historical facts, including statements regarding the following, among others: the anticipated initiation, site activation, patient recruitment, patient enrollment, dosing, generation of data and completion of our adaptive clinical trials, and the announcement of such events; the protocol, design and endpoints of our ongoing and planned clinical trials; the future performance and results of our programs in clinical trials; future preclinical activities and programs; regulatory submissions; the progress and potential benefits of our collaborations with partners; the potential of our preclinical data to predict the behavior of our compounds in humans; our identification and expected timing of future product candidates and their therapeutic potential; the anticipated therapeutic benefits of our potential therapies compared to others; our ability to design compounds using multiple modalities and the anticipated benefits of that model; the potential benefits of PRISM, including our novel PN backbone chemistry modifications, and our stereopure oligonucleotides compared with stereorandom oligonucleotides; the potential benefits of our novel ADAR-mediated RNA editing platform capabilities, including our AIMers, compared to others; anticipated benefits of our proprietary manufacturing processes and our internal manufacturing capabilities; the benefit of nucleic acid therapeutics generally; the strength of our intellectual property; our assumptions based on our balance sheet and the anticipated duration of our cash runway; our intended uses of capital; and our expectations regarding the impact of the COVID-19 pandemic on our business. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including the following: our ability to finance our drug discovery and development efforts and to raise additional capital when needed; the ability of our preclinical programs to produce data sufficient to support our clinical trial applications and the timing thereof; the clinical results of our programs and the timing thereof, which may not support further development of product candidates; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials, including their receptiveness to our adaptive trial designs; our effectiveness in managing future clinical trials and regulatory interactions; the effectiveness of PRISM, including our novel PN backbone chemistry modifications; the effectiveness of our novel ADAR-mediated RNA editing platform capability and our AIMers; the continued development and acceptance of oligonucleotides as a class of medicines; our ability to demonstrate the therapeutic benefits of our candidates in clinical trials, including our ability to develop candidates across multiple therapeutic modalities; our dependence on third parties, including contract research organizations, contract manufacturing organizations, collaborators and partners; our ability to manufacture or contract with third parties to manufacture drug material to support our programs and growth; our ability to obtain, maintain and protect our intellectual property; our ability to enforce our
patents against infringers and defend our patent portfolio against challenges from third parties; competition from others developing therapies for similar indications; our ability to maintain the company infrastructure and personnel needed to achieve our goals; the severity and duration of the COVID-19 pandemic and variants thereof, and its negative impact on the conduct of, and the timing of enrollment, completion and reporting with respect to our clinical trials; and any other impacts on our business as a result of or related to the COVID-19 pandemic, as well as the information under the caption “Risk Factors” contained in our most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) and in other filings we make with the SEC from time to time. We undertake no obligation to update the information contained in this press release to reflect subsequently occurring events or circumstances.
WAVE LIFE SCIENCES LTD.
UNAUDITED CONSOLIDATED BALANCE SHEETS
(In thousands, except share amounts)
| March 31, 2022 | December 31, 2021 | |||||||
| Assets |
||||||||
| Current assets: |
||||||||
| Cash and cash equivalents |
$ | 61,713 | $ | 150,564 | ||||
| Short-term investments |
50,000 | — | ||||||
| Prepaid expenses |
6,940 | 6,584 | ||||||
| Other current assets |
5,730 | 5,416 | ||||||
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|||||
| Total current assets |
124,383 | 162,564 | ||||||
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| Long-term assets: |
||||||||
| Property and equipment, net |
21,046 | 22,266 | ||||||
| Operating lease right-of-use assets |
17,594 | 18,378 | ||||||
| Restricted cash |
3,651 | 3,651 | ||||||
| Other assets |
685 | 148 | ||||||
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| Total long-term assets |
42,976 | 44,443 | ||||||
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| Total assets |
$ | 167,359 | $ | 207,007 | ||||
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| Liabilities, Series A preferred shares and shareholders’ equity (deficit) |
||||||||
| Current liabilities: |
||||||||
| Accounts payable |
$ | 9,853 | $ | 7,281 | ||||
| Accrued expenses and other current liabilities |
7,087 | 14,861 | ||||||
| Current portion of deferred revenue |
36,426 | 37,098 | ||||||
| Current portion of operating lease liability |
5,120 | 4,961 | ||||||
|
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|
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|||||
| Total current liabilities |
58,486 | 64,201 | ||||||
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| Long-term liabilities: |
||||||||
| Deferred revenue, net of current portion |
76,567 | 77,479 | ||||||
| Operating lease liability, net of current portion |
23,617 | 24,955 | ||||||
| Other liabilities |
868 | — | ||||||
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|
|
|
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| Total long-term liabilities |
$ | 101,052 | $ | 102,434 | ||||
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| Total liabilities |
$ | 159,538 | $ | 166,635 | ||||
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| Series A preferred shares, no par value; 3,901,348 shares issued and outstanding at March 31, 2022 and December 31, 2021 |
$ | 7,874 | $ | 7,874 | ||||
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|
|
|
|||||
| Shareholders’ equity (deficit): |
||||||||
| Ordinary shares, no par value; 60,859,968 and 59,841,116 shares issued and outstanding at March 31, 2022 and December 31, 2021, respectively |
$ | 751,229 | $ | 749,851 | ||||
| Additional paid-in capital |
91,951 | 87,980 | ||||||
| Accumulated other comprehensive income |
95 | 181 | ||||||
| Accumulated deficit |
(843,328 | ) | (805,514 | ) | ||||
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|
|
|
|
|||||
| Total shareholders’ equity (deficit) |
$ | (53 | ) | $ | 32,498 | |||
|
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|
|
|
|||||
| Total liabilities, Series A preferred shares and shareholders’ equity (deficit) |
$ | 167,359 | $ | 207,007 | ||||
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|
|
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WAVE LIFE SCIENCES LTD.
UNAUDITED CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS
(In thousands, except share and per share amounts)
| Three Months Ended March 31, | ||||||||
| 2022 | 2021 | |||||||
| Revenue |
$ | 1,750 | $ | — | ||||
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|
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| Operating expenses: |
||||||||
| Research and development |
27,470 | 33,393 | ||||||
| General and administrative |
12,374 | 10,078 | ||||||
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|
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| Total operating expenses |
39,844 | 43,471 | ||||||
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| Loss from operations |
(38,094 | ) | (43,471 | ) | ||||
| Other income, net: |
||||||||
| Dividend income and interest income, net |
26 | 11 | ||||||
| Other income, net |
254 | 996 | ||||||
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| Total other income, net |
280 | 1,007 | ||||||
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| Loss before income taxes |
(37,814 | ) | (42,464 | ) | ||||
| Income tax provision |
— | — | ||||||
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|
|
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|||||
| Net loss |
$ | (37,814 | ) | $ | (42,464 | ) | ||
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| Net loss per share attributable to ordinary shareholders—basic and diluted |
$ | (0.62 | ) | $ | (0.86 | ) | ||
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| Weighted-average ordinary shares used in computing net loss per share attributable to ordinary shareholders—basic and diluted |
60,516,616 | 49,101,606 | ||||||
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| Other comprehensive loss: |
||||||||
| Net loss |
$ | (37,814 | ) | $ | (42,464 | ) | ||
| Foreign currency translation |
(86 | ) | (120 | ) | ||||
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| Comprehensive loss |
$ | (37,900 | ) | $ | (42,584 | ) | ||
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Investor Contact:
Kate Rausch
617-949-4827
krausch@wavelifesci.com
Media Contact:
Alicia Suter
617-949-4817
asuter@wavelifesci.com
Wave Life Sciences Corporate Presentation May 12, 2022 Exhibit 99.2
Forward-looking statements This document contains forward-looking statements. All statements other than statements of historical facts contained in this document, including statements regarding possible or assumed future results of operations, preclinical and clinical studies, business strategies, research and development plans, collaborations and partnerships, regulatory activities and timing thereof, competitive position, potential growth opportunities, use of proceeds and the effects of competition are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause the actual results, performance or achievements of Wave Life Sciences Ltd. (the “Company”) to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “aim,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “potential” or “continue” or the negative of these terms or other similar expressions. The forward-looking statements in this presentation are only predictions. The Company has based these forward-looking statements largely on its current expectations and projections about future events and financial trends that it believes may affect the Company’s business, financial condition and results of operations. These forward-looking statements speak only as of the date of this presentation and are subject to a number of risks, uncertainties and assumptions, including those listed under Risk Factors in the Company’s Form 10-K and other filings with the SEC, some of which cannot be predicted or quantified and some of which are beyond the Company’s control. The events and circumstances reflected in the Company’s forward-looking statements may not be achieved or occur, and actual results could differ materially from those projected in the forward-looking statements. Moreover, the Company operates in a dynamic industry and economy. New risk factors and uncertainties may emerge from time to time, and it is not possible for management to predict all risk factors and uncertainties that the Company may face. Except as required by applicable law, the Company does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.
UNLOCKING THE BODY’S OWN ABILITY TO TREAT GENETIC DISEASE realizing a brighter future for patients and families
Building a leading genetic medicines company ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia; HD: Huntington’s disease; DMD: Duchenne muscular dystrophy; AATD: Alpha-1 antitrypsin deficiency 1stereopure oligonucleotides and novel backbone chemistry modifications Diversified Pipeline CNS: ALS, FTD, HD Muscle: DMD Hepatic diseases: AATD Clinical Expertise Multiple global clinical trials Innovative trial designs Innovative Platform Stereopure oligonucleotides Novel backbone modifications (PN chemistry) Silencing, splicing, and editing modalities Strong and broad IP position1 GMP Manufacturing Internal manufacturing capable of producing oligonucleotides at scale LEVERAGING THE ONGOING genetic revolution Targeting THE TRANSCRIPTOME TO UNLOCK THE BODY’S OWN ABILITY TO TREAT GENETIC DISEASE >6,000 monogenic diseases; vastly more polygenic diseases Increase in genetic testing Biomarkers to assess target engagement early in clinical development Greater understanding of genetic disease and cellular biology Innovations for precise modification of transcriptome, proteome and interactome Many diseases out of reach for traditional medicines
Established regulatory, manufacturing, access and reimbursement pathways Continued progress towards longer dosing intervals while still being reversible and titratable Freely taken up by cells in multiple tissues or compatible with simple ligands – no need for complex delivery vehicles Changes erroneous messages, not erroneous code Strategic focus on intervening at RNA level RNA-targeting therapeutics offer ideal balance of precision, durability, potency, and safety Address underlying genetic drivers of disease Durable effects Defined path to commercialization Simplified delivery
Harnessing the biological machinery in our cells to treat genetic diseases Silencing Splicing RNA Base Editing Degradation of RNA transcripts to turn off protein production Restore RNA transcripts and turn on protein production Efficient editing of RNA bases to restore or modulate protein production Endogenous ADAR enzyme Restored Reading Frame Endogenous RNase H Endogenous AGO2 RISC
Built-for-Purpose Candidates to Optimally Address Disease Biology Silencing | Splicing | RNA Editing DESIGN Unique ability to construct stereopure oligonucleotides and control three structural features to efficiently engage biological machinery OPTIMIZE Provides the resolution to observe this structural interplay and understand how it impacts key pharmacological properties Sequence Stereochemistry Chemistry Unlocking the body’s own ability to treat genetic disease
THERAPEUTIC AREA / TARGET MODALITY DISCOVERY PRECLINICAL CLINICAL RIGHTS NEUROLOGY Takeda 50:50 option ALS and FTD C9orf72 Takeda 50:50 option Huntington’s disease mHTT SNP3 SCA3 ATXN3 CNS diseases Multiple 100% global DMD Exon 53 100% global HEPATIC AATD – lung and liver disease SERPINA1 100% global Robust portfolio of stereopure, PN-modified oligonucleotides ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia; SCA3: Spinocerebellar ataxia 3; CNS: Central nervous system; DMD: Duchenne muscular dystrophy; AATD: Alpha-1 antitrypsin deficiency Therapeutic modality Silencing Splicing ADAR editing (AIMers) WVE-004 (FOCUS-C9) WVE-003 (SELECT-HD) WVE-N531 NEUROLOGY HEPATIC (GalNAc)
WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
C9orf72 repeat expansions: One of the most common genetic causes of ALS and FTD Typically 100’s-1000’s of GGGGCC repeats Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD) Hexanucleotide (G4C2)- repeat expansions in C9orf72 gene are common autosomal dominate cause for ALS and FTD Different manifestations across a clinical spectrum Fatal neurodegenerative disease Progressive degeneration of motor neurons in brain and spinal cord C9-specific ALS: ~2,000 patients in US Progressive neuronal degeneration in frontal / temporal cortices Personality and behavioral changes, gradual impairment of language skills C9-specific FTD: ~10,000 patients in US Including patients with C9-associated ALS, FTD or both Sources: Balendra et al, EMBO Mol Med, 2017; Brown et al, NEJM, 2017, DeJesus-Hernandez et al, Neuron, 2011. Renton et al, Neuron, 2011. Zhu et al, Nature Neuroscience, May 2020, Stevens et al, Neurology 1998
WVE-004 targets repeat-containing transcript variants that lead to production of pathological mRNA products and toxic DPR proteins and loss of normal C9orf72 function, which is important for normal regulation of neuronal function and the immune system Wave selected the poly(GP) DPR because it is a sensitive biomarker of target engagement and reductions of mRNA transcripts and other toxic proteins WVE-004 selectively targets repeat-containing transcripts to address multiple drivers of toxicity Liu et al, Nature Communications, 2021; DPRs: dipeptide repeat proteins pre-mRNA variants Pathological mRNA products V1 V2 Mis-spliced V1/V3 Stabilized intron1 V3 Disease-contributing factors RNA foci DPRs, including poly(GP) GGGGCC (hexanucleotide repeat) expansion WVE-004 unique target knockdown site Reduced by WVE-004 Repeat-containing transcripts C9orf72 gene G4C2 repeat expansion WVE-004 preserves C9orf72 protein
* *** ** *** Spinal cord Relative poly(GP) levels (normalized to PBS) Cortex >90% knockdown of poly(GP) DPR protein Two doses of WVE-004 Six months >80% knockdown of poly(GP) DPR protein Relative poly(GP) levels (normalized to PBS) p≤0.0001 Liu et al., 2022 Molecular Therapy Nucleic Acids doi: 10.1016/j.omtn.2022.04.007; 2 x 50 ug (day 0, day 7) dosed ICV; DPRs measured by poly(GP) MSD assay. *: p≤ 0.05 **: P ≤ 0.01, ***: P ≤ 0.001. DPR: Dipeptide repeat protein Weeks Weeks PBS Poly(GP) DPR Oligonucleotide concentration WVE-004: WVE-004: C9orf72 protein unchanged at 6 months ns ug of oligo / g of tissue ug of oligo / g of tissue ns Relative fold change C9orf72/HPRT1 1.5 0.5 0.0 1.0 Relative fold change C9orf72/HPRT1 1.5 0.5 0.0 1.0 WVE-004 PBS WVE-004 PBS Preclinical studies with WVE-004 demonstrated durable reduction of poly(GP) in spinal cord and cortex 6 months after two doses Preclinical in vivo results:
WVE-004 clinical data demonstrate successful translation of preclinical models to clinic PK: pharmacokinetic PD: pharmacodynamic; Right: *p=0.020, **p=0.008, ***p=0.001, ****p<0.001, % change from baseline. Mixed model for repeated measures used for all statistical testing PK/PD modeling using preclinical in vivo models predicted pharmacodynamically active starting dose Target engagement confirmed in patients supports advancing FOCUS-C9 clinical study Poly(GP) reduction in cortex and spinal cord in transgenic mice with WVE-004 Sufficient concentrations of WVE-004 in cortex and spinal cord of NHP for target engagement Placebo (n=3) WVE-004 10 mg (n=2) WVE-004 30 mg (n=4)
30 mg Optimizing dose level and frequency to enable discussions with regulatory authorities later in 2022 10 mg n=3 60 mg n=4 20 mg 10 mg n=6 4 monthly doses Dose and frequency to be guided by DSMB Expanding n=10 Given poly(GP) reduction with single 30 mg doses that does not appear to have plateaued at day 85, extending observation period and adding additional patients to FOCUS-C9 clinical trial Dosing in a multidose cohort (monthly) at 10 mg is well underway Planning underway for initiation of an open-label extension (OLE) clinical trial in mid-2022 Data planned to be presented in oral presentation at ENCALS Meeting (June 1-3, 2022) Additional single and multidose data for WVE-004 expected throughout 2022 Target engagement observed in single dose cohorts New n=10 Adapting clinical trial to optimize dose level and frequency ENCALS: European Network to Cure ALS Ongoing Phase 1b/2a randomized, double-blind, placebo-controlled trial evaluating patients with C9-ALS, C9-FTD or mixed phenotype
WVE-003 Huntington’s Disease
Healthy individual Huntington’s disease mHTT toxic effects lead to neurodegeneration, loss of wtHTT functions may also contribute to HD Wild-type HTT (wtHTT) is critical for normal neuronal function Expanded CAG triplet repeat in HTT gene results in production of mutant huntingtin protein (mHTT) Huntington’s disease affects entire brain Monogenic autosomal dominant genetic disease; fully penetrant Fatal disease characterized by cognitive decline, psychiatric illness, and chorea Stresses wtHTT Stresses wtHTT mHTT + ~50% decrease in wtHTT Healthy CNS function Synaptic dysfunction | Cell death | Neurodegeneration Loss of wtHTT functions
Plays an essential role in the transport of synaptic proteins—including neurotransmitters and receptors—to their correct location at synapses9-12 Promotes neuronal survival by protecting against stress (e.g., excitotoxicity, oxidative stress, toxic mHTT aggregates)1-8 BRAIN CIRCUITS SYNAPSE NEURON CSF circulation Supplies BDNF to the striatum to ensure neuronal survival13-16 Regulates synaptic plasticity, which underlies learning and memory17-22 Plays a critical role in formation and function of cilia—sensory organelles that control the flow of CSF—which are needed to clear catabolites and maintain homeostasis23 HD: Wild-type HTT is a critical protein for important functions in the central nervous system BDNF, brain-derived neurotrophic factor; CSF, cerebrospinal fluid; mHTT, mutant huntingtin protein. Sources: 1. Leavitt 2006 2. Cattaneo 2005 3. Kumar 2016 4. Franco-Iborra 2020 5. Hamilton 2015 6. Ochaba 2014 7. Wong 2014 8. Rui 2015 9. Caviston 2007 10. Twelvetrees 2010 11. Strehlow 2007 12. Milnerwood 2010 13. Smith-Dijak 2019 14. Tousley 2019 15. Zhang 2018 16. McAdam 2020 17. Altar 1997 18. Zuccato 2001 19. Gauthier 2004 20. Ferrer 2000 21. Baquet 2004 22. Liu 2011 23. Karam 2015
Target SNP3 on mutant mRNA HTT transcript to potentially reduce mutant HTT protein Potential to reserve wild-type HTT protein reservoir in brain WVE-003: Allele-selective approach to treating HD Wave has the only allele-selective clinical program in Huntington’s disease Only an allele-selective approach is designed to address both toxic gain of function and toxic loss of function drivers of HD Stresses wtHTT mHTT + Reduce Preserve
WVE-003 (SNP3) demonstrates selective, potent, and durable reduction of mHTT in preclinical models Selectively reduces mHTT mRNA in HD iPSC neurons in vitro Results from ND50036 iPSC-derived medium spiny neurons. Total HTT knockdown quantified by qPCR and normalized to HPRT1. Oligonucleotide or PBS [100 μg ICV injections through cannula on days 1, 3, 5] delivered to BACHD transgenic. Mean ± SD (n=8, *P<0.0332, ***P<0.0002, ****P<0.0001 versus PBS unless otherwise noted). HPRT1, hypoxanthine-guanine phosphoribosyl transferase; iPSC, induced pluripotent stem cell; ICV, intracerebroventricular; PBS, phosphate-buffered saline Similar results in cortex Pan-silencing reference compound WVE-003 PBS Weeks *** **** **** **** **** **** Pan-silencing reference compound WVE-003 Percentage HTT mRNA Remaining Durable striatal mHTT knockdown for 12 weeks in BACHD mouse model Incorporates PN backbone chemistry modifications
WVE-003: In vivo studies support distribution to cortex and striatum in mice and NHPs PK: pharmacokinetic PD: pharmacodynamic IC50: the concentration of observed half of the maximal effect mHTT: mutant huntingtin protein NHP: non-human primate Achieved sufficient concentrations of WVE-003 in cortex and striatum for target engagement NHP Anticipated mHTT knockdown in cortex and striatum based on PK-PD modeling Human BACHD mouse model Achieved maximum mHTT knockdown of 70-75% in cortex and striatum with ~50% knockdown persisting for at least 3 months with WVE-003 Clinical data to enable decision making expected in 2022
Day 1-3 15 29 57 85 Dose q PK / Biomarker Samples l l l l l Clinical Evaluations l l l l SELECT-HD clinical trial: Dose level and dosing frequency guided by independent committee Dose level and dosing frequency guided by independent committee Single ascending dose Dose Level Cohort 1 Cohort 1 Additional cohorts Proceed to MAD Monthly or less frequent dosing PK / Biomarker samples Clinical evaluations Additional cohorts l l q Safety and tolerability UHDRS Clinical evaluations mHTT wtHTT NfL Key biomarkers: PK: pharmacokinetic Multi-ascending dose Adaptive cohorts
WVE-N531 Duchenne muscular dystrophy
Duchenne muscular dystrophy Duchenne muscular dystrophy Genetic mutation in dystrophin gene prevents the production of dystrophin protein, a critical component of healthy muscle function. Dystrophin protein established by FDA as surrogate endpoint reasonably likely to predict benefit in patients1 for accelerated approval in DMD Confirmatory studies ongoing Increasing amount of functional dystrophin expression over minimal amount shown with approved therapies is expected to result in greater benefit for patients Impacts 1 in every 5,000 newborn boys each year; 20,000 new cases annually worldwide. 1Vyondys: www.fda.gov; viltepso; www.fda.gov; Exondys; www.fda.gov; Amondys: www.fda.gov
PN chemistry improved muscle exposure and survival in preclinical mouse models Kandasamy et al., 2022; doi: 10.1093/nar/gkac018 PN boosted muscle concentrations after single dose, which correlated with exon-skipping activity PN PN Treatment with PN-modified molecules led to 100% survival of dKO mice at time of study termination Better tissue exposure 100 75 50 25 0 Survival probability (%) 0 4 8 12 16 20 24 28 32 36 40 Time (weeks) PS/PO/PN, 75 mg/kg bi-weekly PBS PS/PO, 150 mg/kg weekly PS/PO/PN, 150 mg/kg weekly Note: Untreated, age-matched mdx mice had 100% survival at study termination [not shown]
PS/PO/PN splicing compound restores respiratory function to wild-type levels in dKO mice Kandasamy et al., 2022; doi: 10.1093/nar/gkac018 Wild-type dKO / PBS dKO (PS/PO/PN oligonucleotide) **** **** **** ****
PS/PO/PN compound restores muscle function to wild-type levels in dKO mice dKO / PBS (6 week old) dKO PS/PO/PN, QW 150mpk (38-41 week old) Wild-type (6 week old) Specific Force (EDL) Eccentric Contraction (EDL) Mdx/utr-/- mice received weekly subQ 150 mpk dose of PS/PO/PN stereopure oligonucleotide beginning at postnatal day 10. Age-matched mdx/utr-/- littermates were treated with PBS, and wild-type C57BL10 mice were not treated. Electrophysiology to measure specific force and eccentric contraction performed at Oxford University based on Goyenvalle et al., 2010 Mol Therapy 18(1), 198-205.
WVE-N531: Dystrophin restoration in vitro and enhanced muscle distribution in NHPs Western Blot normalized to primary healthy human myoblast lysate Dystrophin protein restoration of up to 71% in vitro Plasma and tissue concentrations of WVE-N531 (PS/PO/PN) significantly higher than suvodirsen (1st-gen PS/PO) in multiple NHP studies Substantially higher muscle concentrations (including heart and diaphragm) as compared to suvodirsen Higher plasma Cmax, AUC and Ctrough Enhanced muscle distribution in NHPs
Cohort expansion to be guided by assessment of muscle biopsies: (drug distribution in muscle and biomarkers) Dose escalation ongoing in clinical trial of WVE-N531 Open-label clinical trial of boys with DMD amenable to exon 53 skipping Dose level and dosing frequency guided by tolerability and plasma PK DMD: Duchenne muscular dystrophy Ascending intra-patient doses of WVE-N531 Up to 4 dose levels (administered ≥4 weeks apart) evaluated to select dose level for multidose Up to 3 additional doses given every-other-week at selected dose level, followed by muscle biopsy Additional patients enrolled and dosed every other week at selected dose level Up to 7 total doses to be given followed by a minimum 8-week safety monitoring period Powered to evaluate change in dystrophin expression Clinical data, including muscle biopsies, expected in 2022 Initial cohort Possible cohort expansion (up to 15 boys)
WVE-N531 plasma concentrations at starting dose significantly improved over suvodirsen WVE-N531 is designed with PN chemistry backbone modifications. Suvodirsen (first-generation Exon 51 candidate) did not include PN chemistry. NHP: non-human primates; AUC: Area under curve; Cmax: Maximum plasma concentration WVE-N531 Phase 1b/2a open-label clinical trial starting dose Dose escalation is ongoing WVE-N531 plasma half-life estimated to be >1 week (vs. less than 24 hours for suvodirsen) WVE-N531 (PN chemistry) fold increase over suvodirsen at the same dose level Plasma: Cmax ~2.5x AUC ~4x Muscle: Patient muscle biopsies expected in 2022 Increase in plasma concentrations with single dose
AIMers RNA base editing capability
Unlocking RNA editing with PRISM platform to develop AIMers: A-to-I editing oligonucleotides Endogenous ADAR enzymes 1Woolf et al., PNAS Vol. 92, pp. 8298-8302, 1995; Right: Data from independent experiments; Total RNA was harvested, reverse transcribed to generate cDNA, and the editing target site was amplified by PCR and quantified by Sanger sequencing Improved editing PS/PO/PN PS/PO (Stereopure) PS/PO (Stereorandom) Concentration (mM) % ACTB editing ADAR enzymes First publication (1995) using oligonucleotide to edit RNA with endogenous ADAR1 Catalyze conversion of A-to-I (G) in double-stranded RNA substrates A-to-I (G) edits are one of the most common post-transcriptional modifications ADAR1 is ubiquitously expressed across tissues, including liver and CNS Learnings from biological concepts Applied to ASO structural concepts Applied PRISM chemistry AIMer: Wave’s A-to-I editing oligonucleotides Free-uptake of chemically modified oligonucleotides (No need for LNPs or viral vectors) Stereochemistry and PN chemistry enhance potency and editing efficiency of GalNAc AIMers in primary human hepatocytes
AIMers: Realizing potential of therapeutic RNA editing by harnessing endogenous ADAR Solved for key therapeutic attributes for potential best-in-class RNA editing therapeutics Efficient ADAR recruitment AIMer design principles SAR developed to design AIMers for different targets Systematized AIMer design enables rapid advancement of new targets Strong and broad IP in chemical and backbone modifications, stereochemistry patterns, novel and proprietary nucleosides Potent and specific editing in vivo Efficient ADAR recruitment Stability Delivery and intracellular trafficking Beyond liver Decade of investment and learnings to improve stability of single-stranded RNAs GalNAc compatible for targeted liver delivery Endosomal escape and nuclear uptake AIMer design also works for delivery to CNS and other tissue types Potential for infrequent dosing Subcutaneous dosing IT, IVT, systemic dosing
AATD and additional hepatic diseases Neurological disorders (e.g. Rett syndrome) Recessive or dominant genetically defined diseases Cardiometabolic, oncology, immunology AIMer opportunity Correct tens of thousands of pathogenic human SNPs potentially amenable to ADAR editing correction1 Modulate protein interactions, e.g. upregulation of protein expression and disruption of protein-protein interactions Editing: Potent, durable, specific A à I (G) RNA editing Delivery: Efficient RNA editing in preclinical in vivo models: Targeted delivery (GalNAc) Systemic delivery Local delivery (IT, IVT, others) Potential to accelerate timelines to candidate with AIMer pipeline expansion Wave’s AIMers have potential to uniquely address wide array of genetically-defined diseases Monian et al., 2022 Nature Biotech published online Mar 7, 2022 doi: 10.1038.s41587-022-01225-1; SNP: single nucleotide polymorphism A: Adenosine; I: Inosine; G: Guanosine; AATD: alpha-1 antitrypsin disease; 1ClinVar database
Proof-of-concept preclinical RNA editing data published in Nature Biotechnology (March 2022) Monian et al., 2022 published online Mar 7, 2022; doi: 10.1038.s41587-022-01225-1 SAR structure-activity relationship Specificity in vitro & in vivo (NHPs) In vitro-in vivo translation (NHPs) GalNAc conjugation Foundational AIMer SAR
Levels of endogenous ADAR enzyme are not rate limiting for editing Percentage A-to-I editing detected on the indicated transcripts in presence of 20 nM each of a single (Isolated) or multiple (Multiplex) AIMers after transfection of primary human hepatocytes (left). Data are presented as mean ± SEM, n=3. P values as determine by two-tailed Welch’s t-test are indicated. NTC non-targeting control. Monian et al., 2022 published online Mar 7, 2022; doi: 10.1038.s41587-022-01225-1 Endogenous ADAR enzyme supports editing on multiple independent targets Editing efficiency comparable even when additional AIMers targeting different sequences are added, suggesting there is a more than sufficient reservoir of ADAR enzyme Single AIMer Multiple AIMers targeting different sequences “multiplex” ns ns
XAX NNN AIMer mRNA target Sequence space is defined >300 unique AIMers tested containing different base pair combinations Identified base modification combinations with high editing efficiency to optimize sequence Optimization of every dimension to inform future rational design of AIMers Motif on target Motif on AIMer Learnings inform design principles deployed across future targets Example: Sequence is one of multiple dimensions for optimization Heat map for sequence impact on SAR
Stability of AIMers enables durable and specific editing out to Day 50 in liver of NHPs Monian et al., 2022 published online Mar 7, 2022; doi: 10.1038.s41587-022-01225-1 Left: AIMer PK C: 5mg/kg SC: Day 1,2,3,4,5; Liver biopsy; Right: Dosed 1um AIMer, 48 hrs later RNA collected, RNAseq conducted using strand-specific libraries to quantify on / off-target editing; plotted circles represent sites with LOD>3. NHP: non-human primate; ACTB: Beta-actin AIMers detected in liver of NHP at Day 50 (PK) ADAR editing with ACTB AIMer is highly specific ACTB Confidence (LOD score) % Editing RNA editing within full transcriptome (primary human hepatocytes) Substantial and durable editing in NHP liver in vivo (PD) Day 50 RNA editing in NHP RNA editing only detected at editing site in ACTB transcript GalNAc AIMers GalNAc AIMers
Substantial in vivo RNA editing out to at least 4 months post-single dose in CNS tissues Transgenic huADAR mice administered 100 mg AIMer or PBS on day 0 and evaluated for UGP2 editing across CNS tissues at 1, 4, 8, 12, and 16-weeks post dose. Percentage UGP2 editing determined by Sanger sequencing. Stats: 2-way ANOVA compared to PBS (n=5 per time point per treatment) *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. ICV intracerebroventricular; PBS phosphate buffered saline
RNA editing of nonsense mutation found in MECP2 (Rett Syndrome) restores functional protein 293T cells transfected with both nonsense mutation on MECP2 (GFP-fusion construct) and ADAR plasmids. AIMers transfected for 48h prior to RNA extraction and sequencing. Percentage editing determined by Sanger sequencing. Left: Single dose (25nM) treatment Middle: Full dose response curve (25nM, 5-fold dilution, 48h treatment) in presence or absence of hADAR Right: Western blot for MECP2 protein. Three biological replicates, NTC AIMer, mock and naïve 293T cells probed for fusion protein. in vitro ADAR editing of over 60% targeting MECP2 disease transcript Full length MECP2 protein is expressed following ADAR editing Loading Control Endogenous MECP2 ADAR Edited MECP2 Mock Naive NTC Ladder Dose-dependent RNA editing of MECP2 mutation with PS/PN AIMer Control (no hADAR) PS/PN AIMer … CGA… wild type protein … TGA… premature stop codon … TGG… restored protein Normal: Rett Syndrome: ADAR editing: Variant base ADAR editing site Nonsense mutations found in Rett Syndrome can occur in multiple locations on RNA transcript: PN chemistry improved editing efficiency in vitro Dosed with hADAR
(left): non-human primate (NHP) 50 mg/kg beta-Actin (ACTB) AIMer, SC (subcutaneous) on day 1; Necropsy for editing day 8; (top right): Mice received 10 or 50 mg UGP2 AIMer intravitreal (IVT), eye collected for analysis 1 or 4 weeks later. (lower right): Human PBMCs dosed with 10 mM ACTB AIMers, under activating conditions (PHA). After 4 days, different cell types isolated, quantitated for editing. Productive editing beyond liver and CNS with unconjugated AIMers Kidney ACTB AIMer Mock AIMers Kidney, liver, lung, heart Immune cells Editing in NHP 1-week post-single SC dose unconjugated ACTB AIMer Liver Lung Heart % ACTB editing 60 40 20 0 PBS ACTB AIMer CD14 Monocytes CD4+ T-cell CD19 B-cell Tregs T-cell CD8+ T-cell NK NK-cell Ophthalmology 1 week PBS 10 ug 50 ug 10 ug 50 ug PBS %UGP2 mRNA editing 80 60 40 20 0 Durable, dose-dependent editing in mice post-IVT injection of unconjugated UGP2 AIMer 4 weeks Editing in human PBMCs in vitro unconjugated ACTB AIMer
Apply AIMers to modify protein-protein interactions AIMer 1 Control AIMer 2 AIMer 3 AIMer 4 Amino acid substitution Cys Gly Cys Asp Tyr Arg Tyr Asn KEAP1 Edited Percentage editing (293T cells) AIMer 10 Control AIMer 11 AIMer 12 AIMer 13 Percentage editing (293T cells) Arg Val Gly Gly Gln Ile Asp Glu Amino acid substitution NRF2 Edited KEAP1 editing NRF2 editing NRF2 is degraded by proteasome NRF2 KEAP1 Transcription is repressed ADAR editing sites NRF2 is stabilized KEAP1 NRF2 Transcription is activated Basal conditions ADAR-modified conditions % Editing % Editing 293T cells transfected with 20 nM of AIMer, ADAR-p110 or ADAR-p150 plasmid. RNA collected 48h later, editing quantified by PCR and Sanger (n=2).
NRF2-mediated gene transcription ADAR editing activates multiple genes, confirming disrupted protein-protein interaction in vitro KEAP1 NRF2 ADAR editing of either KEAP1 or NRF2 directs gene activation NQO1 Fold increase over control Control Control Fold increase over control Fold increase over control Fold increase over control SLC7a11 SRGN HMOX1 Control Control AIMer 4 AIMer 2 AIMer 3 AIMer 13 AIMer 12 AIMer 11 AIMer 10 AIMer 1 Control Control AIMer 4 AIMer 2 AIMer 3 AIMer 13 AIMer 12 AIMer 11 AIMer 10 AIMer 1 Control Control AIMer 4 AIMer 2 AIMer 3 AIMer 13 AIMer 12 AIMer 11 AIMer 10 AIMer 1 Control Control AIMer 4 AIMer 2 AIMer 3 AIMer 13 AIMer 12 AIMer 11 AIMer 10 AIMer 1 Gene expression quantified by PCR (n=2) after transfection into 293T cells
Alpha-1 antitrypsin deficiency (AATD)
3) Retain M-AAT physiological regulation 2) Reduce Z-AAT protein aggregation in liver RNA editing is uniquely suited to address the therapeutic goals for AATD M-AAT reaches lungs to protect from proteases M-AAT secretion into bloodstream AAT: Alpha-1 antitrypsin Strnad et al., 2020 N Engl J Med 382:1443-55; Blanco et al., 2017 Int J Chron Obstruct Pulmon Dis 12:561-69; Remih et al., 2021 Curr Opin Pharmacol 59:149-56. Wave ADAR editing approach addresses all goals of treatment: PI*MM Normal PI*MZ Low PI*SZ PI*ZZ High (lung + liver) Null (no AAT) Highest risk (lung) Risk of disease Wild-type M-AAT protein replaces Z-AAT with RNA correction Z-AAT 1) Restore circulating, functional wild-type M-AAT ~200K people in US and EU with mutation in SERPINA1 Z allele (PI*ZZ) Current protein augmentation addresses only lung manifestations siRNA approaches only address the liver disease Alternative approaches address only a subset of treatment goals: Small molecule approaches may address the lung and liver but do not generate wildtype M-AAT
RNA editing only detected at PiZ mutation site in SERPINA1 transcript (mouse liver) RNA editing within transcriptome (mouse liver) ADAR editing is highly specific; no bystander editing observed on SERPINA1 transcript SERPINA1 (PiZ mutation site) % Editing Dose 3 x 10mg/kg days (0, 2, 4) SC. Liver biopsies day 7. RNAseq, To quantify on-target SERPINA1 editing reads mapped to human SERPINA1, to quantify off-target editing reads mapped to entire mouse genome; plotted circles represent sites with LOD>3 (N=4); Analyst and Investor Research Webcast September 28, 2021 Coverage Coverage Editing site (PiZ mutation) PBS SA1-4 AIMer C 0% T 100% C 48.2% T 51.8%
PBS Week Preclinical AIMer treatment results in circulating AAT protein levels well above anticipated therapeutic threshold AIMers (SA1-5) administered in huADAR/SERPINA1 mice (8 – 10 weeks old) Left : Total AAT protein quantified by ELISA. Right: Liver biopsies collected at week 19 (one week after last dose) and SERPINA1 editing was quantified by Sanger sequencing ~5-fold increase in AAT protein % SERPINA1 editing (Mean, SEM) 10 mg/kg AIMer dose ~70% wild-type, M-AAT protein in serum with GalNAc-AIMer treatment ~60% RNA editing with GalNAc-AIMer treatment GalNAc-AIMer treatment bi-weekly results in serum AAT protein levels >11 uM at week 19 in transgenic mice 11uM 18.5 uM AIMer Serum AAT protein (µg/ml) (Mean, SEM) AIMer AIMer
AATD AIMer restores functional M-AAT protein and alleviates liver aggregation in preclinical model GalNAc AIMer (SA1-5) administered bi-weekly (10 mg/kg) following initial loading dose (3 x 10 mg/kg) in huADAR/SERPINA1 mice (8–10 weeks old); Left: Neutrophil elastase inhibition assay (pre-dose, week 19 serum samples), Stats: Mixed effects analysis P<0.001; Right: 20x images from liver stained with PAS-D at 19 weeks ** p<0.01 Neutrophil elastase inhibition (Week 19) *** PBS GalNAc AIMer ~3-fold PAS-D staining (19 weeks) GalNAc AIMer PBS Weeks following first dose PAS-D-positive area declines with AIMer treatment ** PBS GalNAc AIMer Correction of gain-of-function phenotypes Restored M-AAT reaches lungs to protect from proteases Wild-type M-AAT protein replaces Z-AAT with RNA correction Correction of loss-of-function phenotypes Z-AAT M-AAT Decreased liver aggregates
GalNAc-AIMers are uniquely suited to address the key treatment goals for AATD https://www.labiotech.eu AIMers RNAi AAT augmentation therapy Restore circulating functional wild-type AAT ü ü Reduce Z-AAT protein aggregation in liver ü ü Retain M-AAT physiological regulation ü Recruit endogenous ADAR enzyme to edit SERPINA1 Z mRNA with high specificity Restore circulating, functional M-AAT protein above expected therapeutic threshold (11 mM) Reduce Z-AAT protein aggregation in liver Expect to select an AATD AIMer development candidate and initiate IND-enabling toxicology studies in 3Q 2022
Wave’s discovery and drug development platform
Wave publications: Current therapeutics with chiral backbone modifications: Enables rational design and optimization of fully-characterized, stereopure RNA therapeutics Wave is the leader in rationally designed stereopure oligonucleotides Stereochemistry is a reality of chemically-modified nucleic acid therapeutics Strong and broad IP portfolio and unique ability to manufacture and screen stereopure oligonucleotides siRNA RNA guide strands Antisense oligonucleotides Exon-skipping oligonucleotides PRISM controls stereochemistry throughout drug discovery and development process Chirality matters: affects pharmacology of oligonucleotides in vitro and in vivo 1Jahns et al., NAR, 2021; Hansen, et al. 2021; Funder, Albaek et al. 2020
… … Innovating stereopure backbone chemistry modifications: PN chemistry Chirality None PN backbone Sp PN backbone Rp Chirality … … PS backbone Rp PS backbone Sp Chirality … … PRISM backbone linkages PO: phosphodiester PS: phosphorothioate -O -S N (Rp) (Sp) PO PS PN Negative charge Neutral charge Negative charge Phosphoryl guanidine x-ray structure example
Improvements in PRISM primary screen hit rates accelerate drug discovery over time Primary screen hit rates with silencing far above industry standard hit rates Stereorandom Chemistry, PN stereochemistry & machine learning optimization Stereopure Chemistry improvements and PRISM advancement All screens used iPSC-derived neurons; Data pipeline for improved standardization. Hit rate = % of oligonucleotides with target knockdown greater than 50%. Each screen contains >100 oligonucleotides. ML: machine learning (2019) (2020 - current)
Silencing Potency is enhanced with addition of PN modifications across modalities Improved knockdown Splicing Editing Improved skipping Ranked by potency of reference PS/PO compound Ranked by potency of reference PS/PO compound Improved editing PS/PO/PN PS/PO (Stereopure) PS/PO (Stereorandom) Concentration (mM) % Editing PS/PO reference compound PS/PN modified compound % Skipping Target knockdown (% remaining) Left: Experiment was performed in iPSC-derived neurons in vitro; target mRNA levels were monitored using qPCR against a control gene (HPRT1) using a linear model equivalent of the DDCt method; Middle: DMD patient-derived myoblasts treated with PS/PO or PS/PO/PN stereopure oligonucleotide under free-uptake conditions. Exon-skipping efficiency evaluated by qPCR. Right: Data from independent experiments
Adding PN chemistry modifications to C9orf72-targeting oligonucleotides improved potency in vivo Exposure (µg/g) Exposure (µg/g) Cortex %C9orf72 V3 transcript remaining Oligonucleotide concentrations quantified by hybridization ELISA. Graphs show robust best fit lines with 95% confidence intervals (shading) for PK-PD analysis; Liu et al. Molecular Therapy Nucleic Acids 2022; Kandasamy et al., Nucleic Acids Research, 2022, doi: 10.1093/nar/gkac037 Spinal Cord C9orf72-targeting oligonucleotides PS/PO backbone chemistry PS/PO/PN backbone chemistry Improved knockdown Improved tissue exposure
PN chemistry improves distribution to CNS NHPs administered 1x12 mg oligonucleotide or PBS by intrathecal injection/lumbar puncture (IT). CNS tissue evaluated 11 or 29 days after injection (n=6 per group). Oligonucleotide was visualized by ViewRNA (red), and nuclei are counterstained with hematoxylin. Images from day 29. Cerebral Cortex Cerebellum Striatum Hippocampus Spinal cord PS/PO PS/PO/PN Backbone chemistry Midbrain Distribution of oligonucleotides in non-human primate CNS 1-month post single IT dose Oligonucleotide (red staining)
Rational design to achieve target engagement and preclinical tolerability Isomer 1 Isomer 2 ns Stereoisomers have similar pharmacodynamic effects in vivo Changing backbone stereochemistry leads to different tolerability profiles in vivo Same sequence, but different backbone stereochemistry Unconjugated oligonucleotide administered ICV Isomer 2 Left: In a target engagement study, 7 mice administered 2 x 50 ug oligonucleotide or PBS by ICV on days 0 and 7. Tissue collected on day 14. Target mRNA normalized to Tubb3 and plotted relative to PBS. Data presented as mean ± SD (n=7). Stats: One-way ANOVA ns not significant, PBS phosphate buffered saline. Right: wt mouse tolerability study, n=4 administered 100 ug oligonucleotide or PBS by ICV on day 0 and monitored for 8 weeks. Percentage Body Weight Change CNS target knockdown in vivo Isomer 1 PBS PBS Isomer 1 Isomer 2 Isomer 3 Isomer 3 Isomer 3
Single intrathecal dose in NHP leads to substantial and widespread target mRNA reduction throughout the CNS NHPs: Non-human primates; NHPs (n=3) received a single 12 mg IT dose of WVE-005. ASO and mRNA quantified by ELISA and qPCR, respectively. Striatum was evaluated in a separate experiment. CTX cortex; HP hippocampus; CSC cervical spinal cord; LSC lumbar spinal cord; STR striatum; aCSF artificial cerebrospinal fluid Target mRNA expression in NHP following administration of WVE-005 (Day 28) Target mRNA normalized to control (aCSF) CTX HP CSC LSC STR aCSF aCSF Potential for infrequent IT administration, widespread CNS distribution of PN modified oligonucleotides, and availability of disease biomarkers facilitates development of differentiated CNS portfolio
*** **** Single dose (3 mg/kg) PRISM PN siRNA loaded in RISC is significantly greater than Adv. ESC siRNA PBS PRISM PN siRNA led to unprecedented silencing as compared to state-of-art >3 months after single dose Adv. ESC siRNA (stereorandom) PRISM PN siRNA (stereopure) ~80% silencing HSD17B13 mRNA in vivo with GalNAc-conjugated PRISM PN siRNA 14 weeks post single dose Better silencing % HSD17B13 mRNA remaining 10-fold 3-fold 65-fold ** ** ** (Left) Proprietary human transgenic mouse model, Post hoc tests derived from Linear Mixed Effects Model with Random subject effects; (Right) ** P<0.01, 2-way ANOVA PRISM PN siRNA (stereopure) Adv. ESC siRNA (stereorandom)
Choose modality to best address genetic target Rapidly develop clinical candidates in reproducible way Scalable, cost-effective manufacturing Genetic code carried by RNA to predict sequence PRISM platform is continuously improving Continuous definition of design principles deployed across programs Design & optimize PN chemistry Stereochemistry Machine learning Predictive modeling In vivo models Iterative analysis of in vitro and in vivo outcomes Platform improves as learnings from each program are applied Silencing Splicing Editing
Established internal GMP manufacturing for multiple oligonucleotide modalities Strong technical knowhow and operating expertise Established infrastructure State of the art facilities (90,000 sq ft) and expansion space Process and analytical development labs GMP oligonucleotide (API) manufacturing Established Quality and GMP systems (QA, supply chain, logistics, QC testing) Experienced team led by Sridhar Vaddeboina, PhD (SVP Chemistry, Manufacturing, Controls) Experts in oligonucleotide synthesis (ASOs, DNAs, RNAs, siRNAs) Proven track record scaling complex chemistries; delivered clinical supply for six programs at Wave Scalable to support Wave’s GMP manufacturing needs, as well as potential new partners
Upcoming milestones
Key anticipated upcoming milestones Additional data generated in 2022 expected to further inform future opportunities and unlock value Silencing CNS (Intrathecal) Splicing Muscle (IV) ADAR editing Targeted delivery liver (Subcutaneous) WVE-004 C9orf72 ALS & FTD Delivered clinical target engagement data with single doses Additional single and multidose data throughout 2022 Discussions with regulatory authorities regarding next phase of development later in 2022 WVE-003 HD SNP3 Clinical data to enable decision making in 2022 WVE-N531 DMD Exon 53 Clinical data to enable decision making in 2022 AATD program SERPINA1 Select an AATD AIMer development candidate and initiate IND-enabling toxicology studies in 3Q 2022 WVE-004 FOCUS-C9 clinical trial (NCT04931862); WVE-003 SELECT-HD clinical trial (NCT05032196); WVE-N531 open-label clinical trial (NCT04906460)
Realizing a brighter future for people affected by genetic diseases For more information: Kate Rausch, Investor Relations krausch@wavelifesci.com 617.949.4827