Frequency Therapeutics Corporate Overview - September 2020
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FORWARD-LOOKING STATEMENTS AND OTHER DISCLAIMERS This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this presentation that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding the treatment potential of FX-322, the design and enrollment of the Phase 2a clinical trial of FX-322, the timing of top-line data from the Phase 2a clinical trial and timing of presentation of results of the exploratory study in Germany, the novelty of the exploratory study in Germany, the implications of the results of the exploratory Germany study in combination with our other trials, the therapeutic levels of FX-322 predicted in the exploratory Germany study, the results and implications of the Phase 1/2 durability of response data, the timing of the FX-322 clinical study in patients with age related hearing loss, the ability of our technology platform to provide patient benefit, the impact of COVID-19 on the Company’s on-going and planned clinical trials and business, future milestone and royalty payments under the license and collaboration agreement with Astellas Pharma Inc. (“Astellas”), the sufficiency of the Company’s cash, cash equivalents and short- term investments, estimates of the size of the hearing loss population and population at risk for hearing loss, the timing of the remyelination program, and the potential application of the PCA platform to other diseases. These forward-looking statements are based on management’s current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: Frequency Therapeutics (the “Company”) has incurred and will continue to incur significant losses and is not and may never be profitable; need for additional funding to complete development and commercialization of any product candidate; the Company’s dependence on the development of FX-322; the unproven approach of the PCA platform; the lengthy, expensive and uncertain process of clinical drug development and regulatory approval; limited experience successfully obtaining marketing approval for and commercializing product candidates; the results of earlier clinical trials not being indicative of the results from later clinical trials; differences between preliminary or interim data and final data; adverse events or undesirable side effects; disruptions at the FDA and other regulatory agencies; the impact of the COVID-19 impact; failure to identify additional product candidates; new or changed legislation; failure to maintain Fast Track designation for FX-322 and such designation failing to result in faster development or regulatory review or approval; costly and damaging litigation, including related to product liability, intellectual property or brought by stockholders; dependence on Astellas for the development and commercialization of FX-322 outside of the United States; misconduct by employees or independent contractors; reliance on third parties, including to conduct clinical trials and manufacture product candidates; compliance with laws and regulations, including healthcare and environmental, health, and safety laws and regulations; failure to obtain, maintain and enforce protection of patents and other intellectual property; security breaches or failure to protect private personal information; attracting and retaining key personnel; and ability to manage growth. These and other important factors discussed under the caption “Risk factors” in the Company’s Form 10-Q filed with the Securities and Exchange Commission (SEC) on August 12, 2020 and its other reports filed with the SEC could cause actual results to differ materially from those indicated by the forward-looking statements made in this presentation. Any such forward-looking statements represent management’s estimates as of the date of this presentation. While the Company may elect to update such forward-looking statements at some point in the future, it disclaims any obligation to do so, even if subsequent events cause its views to change. These forward-looking statements should not be relied upon as representing the Company’s views as of any date subsequent to the date of this presentation. Copyright Frequency Therapeutics, Inc. 2
Frequency Today FX-322 program for sensorineural hearing loss in Phase 2a clinical development • Phase 2a study ongoing, fully enrolled; read out in Q2 2021 • Phase 1/2 results provided evidence of hearing restoration; favorable safety profile • Planning for near-term FX-322 studies in additional patient populations • FDA Fast Track designation Additional opportunities across multiple degenerative diseases • Multiple sclerosis program advancing toward IND; target submission H2 2021 • Broad IP portfolio in hearing and additional applications Operating runway into 2023 • $195.4 million in cash, cash equivalents and short-term investments (as of June 30, 2020) • $40.1 million in net proceeds raised in private placement in July 2020 • Potential development milestones related to Astellas ex-US FX-322 collaboration including $90M at first Phase 2b dosing in Europe & Asia and $140M for the first Phase 3 dosing in Europe & Asia Copyright Frequency Therapeutics, Inc. 3
Key Recent Advances in FX-322 Clinical Development Data presented Sept. 13, 2020 Demonstration of effective delivery to the Preliminary evidence of target tissue longer-term durability • Exploratory study of patients undergoing cochlear • Post P1/2 study word recognition (WR) data impact surgery to determine if cochlear drug obtained in five patients 13- 21 months following levels can be directly measured administration • 4/5 subjects maintained improvements in WR Key findings: scores • Measurement of cochlear fluid confirmed • Three of four patients who responded to FX- successful drug delivery to cochlea in all samples 322 maintained stat sig benefit analyzed • 87% average increase from original baseline • Drug levels predicted to result in • Same three subjects showed 10-15 dB therapeutic activity improvements at 8kHz Copyright Frequency Therapeutics, Inc. 4
Origins of Frequency Therapeutics Tissue-Specific, Pre-programmed Stem Cells Decoding Intestinal Enabling Cochlear Frequency Regeneration Regeneration Therapeutics Langer and Karp publish Same cues reactivate Small molecule small molecules activate normally inactive therapeutics show clinical intestinal progenitors progenitors in the cochlea proof of concept Niche-independent high- Clonal Expansion of Lgr5-Positive purity cultures of Lgr5+ Cells from Mammalian Cochlea and intestinal stem cells and High-Purity Generation of Sensory their progeny Hair Cells Copyright Frequency Therapeutics, Inc. 5
Regenerative Approach with Broad Potential Brain Ear Eye Lung Skin Progenitor cells are stem cells that are pre-programmed to Intestine Bone perform a specific activity Muscle Cartilage Potential to address a range of degenerative diseases Copyright Frequency Therapeutics, Inc. 6
Frequency Progenitor Cell Activation (PCA) Approach Inactive Progenitor Cell Inactive ACTIVATED Progenitor Progenitor Asymmetric division using native programs Functional Target Cell Combinations of small molecules designed to activate progenitor cells Copyright Frequency Therapeutics, Inc. 7
Reducing the Complexity of Regenerative Medicine Harnessing No Change Ease of Innate Biology To Genome Manufacturing Progenitors already Activating native programs, Use of small located within target reducing safety concerns molecules: no need to tissue remove or grow cells ex vivo Copyright Frequency Therapeutics, Inc. 8
Our Pipeline DISCOVERY PRECLINICAL PHASE 1 PHASE 2 PHASE 3 Sensorineural hearing loss (FX-322) DISCOVERY PRECLINICAL PHASE 1 PHASE 2 PHASE 3 Multiple Sclerosis Copyright Frequency Therapeutics, Inc. 9
Cochlear Function: Hearing Different Frequencies Healthy Cochlea » Oval window base Schematic of expanded cochlea Apex Round window 20,000 Hz 1,500 Hz 20 Hz (high frequency) (medium frequency) (low frequency) Copyright Frequency Therapeutics, Inc. 11
Impact of Damage to Cochlear Hair Cells Healthy Cochlea Damaged Cochlea Inner Hair Cells (IHCs) Outer Hair Cells (OHCs) “Analysis of hair cells, auditory nerve fibers and strial tissues … shows that the degree of hearing loss is well predicted from the amount of hair cell loss.” Journal of Neuroscience, July 2020 Copyright Frequency Therapeutics, Inc. DOI: https://doi.org/10.1523/JNEUROSCI.0937-20.2020 12
Profound, Unexpected Synergy Cochlear Progenitor Proliferation (Lgr5-GFP) Culture Media Strong synergy seen between Wnt Activation (glycogen synthase kinase-3 pathways activated (GSK3) Inhibitor; NCE) by small molecules HDAC Inhibition (sodium valproate) Wnt Activation and HDAC inhibition HDAC = Histone deacetylase HIGH SYNERGY In vitro mouse model testing NCE = new chemical entity Copyright Frequency Therapeutics, Inc. Cell Rep. 2017 Feb 21;18(8):1917-1929. doi: 10.1016/j.celrep.2017.01.066 13
FX-322 Program: Aiming to Repair Underlying Pathology • Progenitors in place despite loss of hair cells • FX-322 molecules aim to activate genetic pathways to regenerate missing hair cells Copyright Frequency Therapeutics, Inc. 14
Strong Pre-Clinical Validation Test Outcome In vitro Adult human inner ear tissue Created new hair cells In vivo Restored hair cells and hearing across all Adult deafened mice frequencies Achieved active levels in the cochlea Therapeutic drug levels in multiple species Copyright Frequency Therapeutics, Inc. 15
Clinical Program Copyright Frequency Therapeutics, Inc. 16
FX-322 Administration and Concentration Quick intratympanic injection into the middle ear FX-322 concentrates in the highest frequency region, critical for sound clarity 1,000 Hz 2,000 Hz Inner ear 500 Hz 3,000 Hz Cochlea 250 Hz Middle ear 20,000 Hz Needle 4,000 Hz Outer ear 16,000 Hz Ear drum Round window 14,000 Hz 12,000 Hz Eustachian tube 10,000 Hz 8,000 Hz 6,000 Hz US Phase 1/2 Study FX-322-201 Copyright Frequency Therapeutics, Inc. Analysis in partnership with Mass Eye and Ear Institute Temporal Bone Bank 17
Hearing is Measured Using Validated Tests Audibility (Loudness) Intelligibility (Clarity) measured with pure tones measured with word recognition and words-in-noise tests Word Recognition Test: • List of 50 monosyllabic words • Single words played in quiet Words-in-Noise Test: • Standard, clinically accepted measure • Background noise from multiple voices • Played at different signal-to- noise ratios Copyright Frequency Therapeutics, Inc. 18
Critical Information Lost at High Frequencies “Oh say can you see … by the dawn’s early light” 20 16 Spectrogram Frequency (kHz) 12 of Sound 8 4 0.5 1 1.5 2 2.5 3 Time (Secs) Copyright Frequency Therapeutics, Inc. Source: Monson et al (2014) The perceptual significance of high-frequency energy in the human voice. Frontiers in Psychology, 5, 587 19
Successful Phase 1/2 Study Completed Screening NIHL/SSNHL Mild to Moderately Severe Study Overview • Safety in patients with Single No sensorineural hearing loss Injection Injection FX-322 Placebo • Stable patients N = 15 N=8 15 drug, All 23 8 placebo patients • Assessed hearing by word Day 1 | Dose testing and pure tones Follow-up Visits Days 15, 30, 60, 90 Copyright Frequency Therapeutics, Inc. 20
Clinically Meaningful Improvement in Word Recognition Mild Hearing Loss Moderate to Moderately Severe Hearing Loss • 14 patients (5 placebo) • 9 patients (3 placebo) • Typically very high word recognition scores (45+ words) • All treated subjects showed increases in word recognition • Ceiling effect: Limited room for improvement • 4 of 6 showed statistically significant and clinically meaningful improvement • No change in placebo • No change in untreated ear Copyright Frequency Therapeutics, Inc. 21
Clinically Meaningful Improvements in Word Recognition Absolute Word Recognition Scores 50 47 * 40 Clarity of Sound 39 * 38 Used word tests 30 34 * in a quiet background 29 26 20 Baseline – Correct 20 words out of 50 16 * 14 10 12 Day 90 – Correct words out of 50 7 8 0 Test/retest variability is one Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 standard deviation, which for a 50- word list is ~ 3 words *Statistically significant and clinically meaningful improvements in word recognition Copyright Frequency Therapeutics, Inc. 22
Statistically Significant Improvement in Sound Clarity Word Recognition 50 40 Clarity of Sound Improvement 30 Used word tests % Change from Baseline in a quiet background 20 [all patients] 10 Placebo 0 FX-322 -10 p=0.010 -20 0 Day 15 15 Day 3030 45 Day 6060 75 Day9090 Copyright Frequency Therapeutics, Inc. US Phase 1/2 Study FX-322-201 23
Clear Improvement Trend in Words-in-Noise Words-in-Noise 40 Clarity of Sound Improvement 30 Used word tests % Change from Baseline 20 in a noisy background [all patients] 10 Placebo 0 FX-322 -10 p=0.211 -20 0 10 Day 15 20 30 Day 30 40 50 Day 6060 70 80 Day 90 90 Copyright Frequency Therapeutics, Inc. US Phase 1/2 Study FX-322-201 24
Pure Tone Improvements at Highest Tested Frequency Percent of Patients with 10dB Improvement at 8000 Hz 4 / 13 35% subjects 30% Loudness of Sound measured pure tones 25% 20% • Standard frequency range was 15% measured (500 – 8000 Hz) 10% • Consistent pure tone 0/7 improvements observed at 5% subjects 8000 Hz in only FX-322 subjects 0% Placebo FX-322 Analysis includeds subjects with a measurable baseline hearing deficit at 8000 Hz Copyright Frequency Therapeutics, Inc. US Phase 1/2 Study FX-322-201 25
New Data Show Sustained, Clinically Meaningful Improvements in Word Recognition Absolute Word Recognition Scores 50 50W Clarity of Sound 47 50W Used word tests 40 25W* 39 50W in a quiet background 50W 50W 38 38 34 25W* 35 30 50W Baseline – Correct 30 50W 29 50W words out of 50 26 50W Day 90 – Correct 20 22 words out of 50 50W 20 50W 16 50W 1-2 years – Correct 14 words out of 50 10 12 50W Month 7 Month Month Month Month Test/retest variability is one 16** 21** 19** 13** 21** standard deviation, which for a 50- 0 word list is ~ 3 words Subject 1 Subject 2 Subject 3 Subject 4 Subject 5 *25W = 25 Word test performed outside an official study site at 13-18 months after dosing; results scaled to 50 words 50W = 50 Word test performed under a formal protocol at original study site at 18-21 months after dosing **Since FX-322 dosing Copyright Frequency Therapeutics, Inc. 26
New Data Show Sustained, Clinically Meaningful Improvements in Word Recognition • Follow-up study data presented at Sept. 2020 American Academy of Otolaryngology (AAO) Annual Meeting • Hearing signal observed in subjects from previous Phase 1/2 study appears to be maintained • 4/5 subjects maintained improvements in WR scores • 3/4 subjects showed Thornton-Raffin improvements and had an 87% average increase from original baseline • These same 3 subjects showed 10-15 dB improvements at 8kHz Copyright Frequency Therapeutics, Inc. 27
Clinical Data Confirms FX-322 Delivery to Cochlea • Exploratory study in Germany to see if cochlear drug levels can be directly measured • Patients undergoing cochlear implant surgery receive standard FX-322 injection • Cochlear fluid (perilymph) obtained Key findings: • Measurement of cochlear fluid confirmed successful drug delivery to cochlea in all samples analyzed • Drug levels predicted to result in therapeutic activity Taken together with Phase 1/2 study, we believe this is the first known evidence of a pharmacokinetic / pharmacodynamic effect of a potential hearing restoration therapeutic Copyright Frequency Therapeutics, Inc. 28
Key Elements in FX-322 Development: Leadership in Hearing Drug Development Effective Favorable Clinically meaningful Preliminary evidence delivery to the safety profile improvements in of longer-term target tissue hearing function durability Copyright Frequency Therapeutics, Inc. 29
Phase 2a Study – Objectives Further establish Evaluate Clarify endpoints and hearing signal repeat dosing patient population Copyright Frequency Therapeutics, Inc. 30
FX-322 Study - Phase 2a Design Screening NIHL/SSNHL Mild to Moderately Severe • Double-blind, placebo-controlled, multi-center, adults ages 18-65 • All subjects have meaningful Randomize 1:1:1:1 word recognition deficits • Efficacy and exploratory endpoints • Word recognition FX-322 FX-322 FX-322 Placebo • Words-in-noise 1X 2X 4X 4X N = 24 N = 24 N = 24 N = 24 • Pure tone audiometry (0.25-16kHz) • Tinnitus questionnaire • QoL questionnaires Follow-up Visits Days 15, 30, 60, 90, 120, 150, 180, 210 Copyright Frequency Therapeutics, Inc. 31
Hearing Loss Overview Copyright Frequency Therapeutics, Inc. 32
Improvement in Hearing Clarity is the Major Unmet Need Among Hearing Loss Patients “I can hear you… I just can’t understand you.” Copyright Frequency Therapeutics, Inc. 33
Opportunity to Treat Substantial Patient Population (US) 2018 Hearing Loss Prevalence – US Adults • ~40m SNHL patients – expected 30 26 to grow by 20% by 2030 = not treated = treated with hearing aids • Opportunity to treat patients Patients (millions) 20 both with and without hearing 15 aids 10 • Significant opportunity to expand treatment rate among mild patients 0 Mild Moderate / Severe • No restorative therapies exist to Hearing Loss Hearing Loss treat underlying cause of SNHL Notes: Prevalence based on self-reported hearing loss; sensorineural accounts for >90% of hearing loss Source: National Health Interview Survey (sample size of 35,000 households); Census Bureau; NIH; NCBI Copyright Frequency Therapeutics, Inc. 34
Commercial Overview Introduction of an injectable therapeutic for hearing loss will require ear, nose and throat (ENT) doctors for prescription and administration, while continuing to drive diagnosis and monitoring through audiologists CURRENT STATE FUTURE STATE • FX-322 aims to improve hearing for • Hearing aids are the primary treatment those with acquired SNHL including for hearing loss; limited in reaching overall sound clarity, a major unmet frequencies that impact sound clarity need for hearing loss patients • ENTs have no approved treatment interventions to offer mild, moderate, or • Procedure would be integrated into moderately severe hearing loss patients existing ENT office practices for patients with or without hearing aids • Audiologists are the primary source of • Audiologists role in diagnosing hearing diagnosis, treatment and monitoring loss and patient engagement likely to Only half of hearing loss pts have grow with increased treatment options been formally diagnosed/treated in part due to a lack of available treatment options* Frequency’s focus includes market insight generation, planning & development, and stakeholder engagement Confidential Copyright | Frequency Therapeutics, Inc. 35 *CDC/NCHS 35
Hearing Health Impacts Brain Health July, 2020 Risks Associated with Hearing loss is the largest potentially modifiable risk factor for developing dementia Untreated Hearing Loss 50% 41% DEMENTIA DEPRESSION JAMA Nov 8, 2018 Deal J, et al. Incident Hearing Loss and Comorbidity. A Longitudinal Administrative Claims Study. Copyright Frequency Therapeutics, Inc. 36
Broad Potential of Progenitor Cell Activation Approach Copyright Frequency Therapeutics, Inc. 37
Remyelination Program for Multiple Sclerosis Building on strong progenitor Target IND submission biology foundation in 2H21 • Scripps Institute applied PCA • Building on expertise in discovering approach to brain progenitors and developing synergistic combinations of small molecules • Validated in multiple animal models • Worldwide license and ongoing • Clinically validated using a single research partnership with Scripps agent (Lancet Dec ’17) Copyright Frequency Therapeutics, Inc. 38
Moving Forward Copyright Frequency Therapeutics, Inc. 39
Summary + + Hearing Signal Established Large Market Potential first-in-class regenerative Addressable market treatment to restore hearing of >30 million people in the U.S. + + Ex-US Partnership Platform Potential Global development and PCA platform with potential commercial partner; substantial to treat patients with numerous royalties and milestones, degenerative diseases U.S. rights retained Copyright Frequency Therapeutics, Inc. 40
Appendix Copyright Frequency Therapeutics, Inc. 41
Uniqueness of Our PCA Approach Previous approaches Frequency’s PCA approach Stem cell Pluripotent Multipotent Yamanaka 4 factors Partial reprogramming Bipotent Transdifferentiation Fully differentiated Hair Progenitor Hair Progenitor cell cell cell cell Copyright Frequency Therapeutics, Inc. Based on Conrad Waddington’s Epigenetic Landscape 42
Progenitors in Place to Replace Hair Cell Loss Human Cochlear Cross-section Audiogram Hearing loss correlates with hair cell loss Normal Ion Transport Despite Hair Cell Loss, Progenitor Cells Remain Normal Nerve Function 47 Year Old Male with Occupational Noise Deafness Copyright Frequency Therapeutics, Inc. Analysis in Partnership with Mass Eye and Ear Institute Temporal Bone Bank 43
Astellas Collaboration • Development and commercialization collaboration for FX-322, including lifecycle improvements • Astellas has ex-US rights; Frequency retains US rights to FX-322 • Payments of up to $625mm which included $80mm upfront – Development milestone payments to Frequency of $65.0 million and $25.0 million upon the first dosing of a patient in a Phase 2b clinical trial for SNHL in Europe and Asia, respectively – $100.0 million and $40.0 million upon the first dosing of a patient in a Phase 3 clinical trial for SNHL in Europe and Asia, respectively • Development & commercialization: – Astellas responsible for execution and costs of ex-US clinical development and commercialization • Strategic commitment to invest in ENT as a therapeutic area • Research focus in regenerative medicine • Global footprint in major markets and distributorship model in Africa/ME and LATAM Copyright Frequency Therapeutics, Inc. 44
Proven Leadership Team David Lucchino Chris Loose, Ph.D. Carl Lebel, Ph.D. President, CEO & Co-Founder Chief Scientific Officer & Co-Founder Chief Development Officer Former CEO of Entrega Bio (PureTech). Co- Co-founder/CTO of Semprus BioSciences through Chief Scientific Officer of Otonomy (2009 to founder/CEO of Semprus BioSciences (acquired), FDA/CE clearance and acquisition. Princeton, MIT, 2016). Executive Director, Amgen. Scientific Polaris Partners. MIT Sloan Fellow. Hertz Fellow and Yale Faculty. fellow of the American Academy of Otolaryngology. Dana Hilt, M.D. William Chin, M.D. Will McLean, Ph.D. Chief Medical Officer EVP, Clinical & Translational Science VP, Biology & Regen. Med, Co-Founder Neurologist and neuroscientist with two decades SVP, Discovery Research and Clinical Investigation 15 years experience in inner ear biology. in biopharma and CNS drug development. at Eli Lilly, EVP at PhRMA, Executive Dean for Discovered specific stem cells that make hair Amgen, Lysosomal, Forum Pharma. Research at Harvard Medical School. cells and neurons. Harvard-MIT Health Sciences and Technology Program. Copyright Frequency Therapeutics, Inc. 45
Hearing Clinical Advisory Board Dan Lee, M.D. Rene Gifford, Ph.D. Steve Rauch, M.D. Ruth Litovsky, Ph.D. Director, Pediatric Otology Associate Director of Director, Vestibular Division, Professor, Communications and Neurotology, Pediatric Audiology, Director Medical Director, Mass. Eye Sciences and Disorders and Mass Eye and Ear of Cochlear Implant Program, and Ear Balance and Surgery Division of Otolaryngology, Vanderbilt University Vestibular Center University of Wisconsin Chris Runge, Ph.D. David Friedland, M.D., Ph.D. Julie Arenberg, MS, Ph.D. Joni Doherty, MD, Ph.D. Chief of the Division of Vice-Chair of the Department of Associate Director of Clinical Assistant Professor of Clinical Communication Sciences, Otolaryngology and Audiology for Research and Otolaryngology-Head and Neck Medical College of Wisconsin Communications Sciences, Education, Mass Eye and Ear Surgery, Keck School of Medicine Medical College of Wisconsin of USC. Copyright Frequency Therapeutics, Inc. 46
Regenerative Medicine Advisory Board Jeff Karp, Ph.D. Robert Langer, SC.D. Robin Franklin, Ph.D. Sheng Ding, Ph.D. Associate Professor at David H. Koch Institute Professor Professor of Stem Cell Medicine, Senior Investigator, Gladstone Brigham and Women’s Hospital, at the Massachusetts Institute Wellcome Trust-MRC Cambridge Institute of Cardiovascular Disease Harvard Medical School of Technology Stem Cell Institute Sean J. Morrison, Ph.D. Siddhartha Mukherjee, Amy Wagers, Ph.D. Director of the Children's Medical Center M.D., D.Phil. Forst Family Professor of Research Institute, Assistant Professor of Medicine, Stem Cell and Regenerative Biology, UT Southwestern Columbia University Medical Center Harvard University Copyright Frequency Therapeutics, Inc. 47
Frequency Therapeutics Corporate Overview September 2020 Copyright Frequency Therapeutics, Inc. 48
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