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Category Archives: Genetic Therapy

ROCKET PHARMACEUTICALS : Management’s Discussion and Analysis of Financial Condition and Results of Operations (form 10-Q) – marketscreener.com

You should read the following discussion and analysis of our financial conditionand results of operations together with the condensed consolidated financialstatements and related notes that are included elsewhere in this QuarterlyReport on Form 10-Q and our Annual Report on Form 10-K for the fiscal year endedDecember 31, 2019 filed with the U.S. Securities and Exchange Commission, or theSEC, on March 6, 2020, or our 2019 Form 10-K. This discussion containsforward-looking statements based upon current plans, expectations and beliefsthat involve risks and uncertainties. Our actual results may differ materiallyfrom those anticipated in these forward-looking statements as a result ofvarious factors, including, but not limited to, those discussed in the sectionentitled "Risk Factors" and elsewhere in this Quarterly Report on Form 10-Q. Inpreparing this MD&A, we presume that readers have access to and have read theMD&A in our 2019 Form 10-K, pursuant to Instruction 2 to paragraph (b) of Item303 of Regulation S-K. Unless stated otherwise, references in this QuarterlyReport on Form 10-Q to "us," "we," "our," or our "Company" and similar termsrefer to Rocket Pharmaceuticals, Inc.

We are a clinical-stage, multi-platform biotechnology company focused on thedevelopment of first, only and best-in-class gene therapies, with directon-target mechanism of action and clear clinical endpoints, for rare anddevastating diseases. We currently have three clinical-stage ex vivo lentiviralvector ("LVV") programs currently enrolling patients in the US and EU forFanconi Anemia ("FA"), a genetic defect in the bone marrow that reducesproduction of blood cells or promotes the production of faulty blood cells,Leukocyte Adhesion Deficiency-I ("LAD-I"), a genetic disorder that causes theimmune system to malfunction and Pyruvate Kinase Deficiency ("PKD"), a rare redblood cell autosomal recessive disorder that results in chronic non-spherocytichemolytic anemia. Of these, both the Phase 2 FA program and the Phase 1/2 LAD-Iprogram are in registration-enabling studies in the US and EU. In addition, inthe US we have a clinical stage in vivo adeno-associated virus ("AAV") programfor Danon disease, a multi-organ lysosomal-associated disorder leading to earlydeath due to heart failure. Finally, we have a pre-clinical stage LVV programfor Infantile Malignant Osteopetrosis ("IMO"), a genetic disorder characterizedby increased bone density and bone mass secondary to impaired bone resorption -this program is anticipated to enter the clinic in 2020. We have globalcommercialization and development rights to all of these product candidatesunder royalty-bearing license agreements. Additional work in the discovery stagefor an FA CRISPR/CAS9 program as well as a gene therapy program for the lesscommon FA subtypes C and G is ongoing.

Recent Developments

On February 20, 2020, we entered into separate, privately negotiated exchangeagreements (the "Exchange Agreements") with certain holders of our outstanding5.75% Convertible Senior Notes due 2021 (the "2021 Convertible Notes") to extendthe maturity date by one year. Pursuant to the Exchange Agreements, we exchangedapproximately $39.35 million aggregate principal amount of the 2021 ConvertibleNotes (which represents approximately 76% of the aggregate outstanding principalamount of the 2021 Convertible Notes) for (a) approximately $39.35 millionaggregate principal amount of 6.25% Convertible Senior Notes due August 2022(the "2022 Convertible Notes") (an exchange ratio equal to 1.00 2022 ConvertibleNote per exchanged 2021 Convertible Note) and (b) $119,416 in cash to pay theaccrued and unpaid interest on the exchanged 2021 Convertible Notes from, andincluding, February 1, 2020 to February 20, 2020. The 2022 Convertible Noteswere issued in private placements exempt from registration in reliance onSection 4(a) (2) of the Securities Act of 1933, as amended (the "SecuritiesAct"). Upon completion of the exchange transactions, approximately $12.65million aggregate principal amount of 2021 Convertible Notes remainedoutstanding.

Gene Therapy Overview

Genes are composed of sequences of deoxyribonucleic acid ("DNA"), which code forproteins that perform a broad range of physiologic functions in all livingorganisms. Although genes are passed on from generation to generation, geneticchanges, also known as mutations, can occur in this process. These changes canresult in the lack of production of proteins or the production of alteredproteins with reduced or abnormal function, which can in turn result in disease.

Gene therapy is a therapeutic approach in which an isolated gene sequence orsegment of DNA is administered to a patient, most commonly for the purpose oftreating a genetic disease that is caused by genetic mutations. Currentlyavailable therapies for many genetic diseases focus on administration of largeproteins or enzymes and typically address only the symptoms of the disease. Genetherapy aims to address the disease-causing effects of absent or dysfunctionalgenes by delivering functional copies of the gene sequence directly into thepatient's cells, offering the potential for curing the genetic disease, ratherthan simply addressing symptoms.

We are using modified non-pathogenic viruses for the development of our genetherapy treatments. Viruses are particularly well suited as delivery vehiclesbecause they are adept at penetrating cells and delivering genetic materialinside a cell. In creating our viral delivery vehicles, the viral (pathogenic)genes are removed and are replaced with a functional form of the missing ormutant gene that is the cause of the patient's genetic disease. The functionalform of a missing or mutant gene is called a therapeutic gene, or the"transgene." The process of inserting the transgene is called "transduction."Once a virus is modified by replacement of the viral genes with a transgene, themodified virus is called a "viral vector." The viral vector delivers thetransgene into the targeted tissue or organ (such as the cells inside apatient's bone marrow). We have two types of viral vectors in development, LVVand AAV. We believe that our LVV and AAV-based programs have the potential tooffer a long-lasting and significant therapeutic benefit to patients.

Gene therapies can be delivered either (1) ex vivo (outside the body), in whichcase the patient's cells are extracted and the vector is delivered to thesecells in a controlled, safe laboratory setting, with the modified cells thenbeing reinserted into the patient, or (2) in vivo (inside the body), in whichcase the vector is injected directly into the patient, either intravenously("IV") or directly into a specific tissue at a targeted site, with the aim ofthe vector delivering the transgene to the targeted cells.

We believe that scientific advances, clinical progress, and the greaterregulatory acceptance of gene therapy have created a promising environment toadvance gene therapy products as these products are being designed to restorecell function and improve clinical outcomes, which in many cases includeprevention of death at an early age.

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The chart below shows the current phases of development of Rocket's programs andproduct candidates:

LVV Programs. Rocket's LVV-based programs utilize third-generation,self-inactivating lentiviral vectors to target selected rare diseases.Currently, Rocket is developing LVV programs to treat FA, LAD-I, PKD, and IMO.

Fanconi Anemia Complementation Group A (FANCA):

FA, a rare and life-threatening DNA-repair disorder, generally arises from amutation in a single FA gene. An estimated 60 to 70% of cases arise frommutations in the Fanconi-A ("FANCA") gene, which is the focus of our program. FAresults in bone marrow failure, developmental abnormalities, myeloid leukemiaand other malignancies, often during the early years and decades of life. Bonemarrow aplasia, which is bone marrow that no longer produces any or very few redand white blood cells and platelets leading to infections and bleeding, is themost frequent cause of early morbidity and mortality in FA, with a median onsetbefore 10 years of age. Leukemia is the next most common cause of mortality,ultimately occurring in about 20% of patients later in life. Solid organmalignancies, such as head and neck cancers, can also occur, although at lowerrates during the first two to three decades of life.

Although improvements in allogeneic (donor-mediated) hematopoietic stem celltransplant ("HSCT"), currently the most frequently utilized therapy for FA, haveresulted in more frequent hematologic correction of the disorder, HSCT isassociated with both acute and long-term risks, including transplant-relatedmortality, graft versus host disease ("GVHD"), a sometimes fatal side effect ofallogeneic transplant characterized by painful ulcers in the GI tract, livertoxicity and skin rashes, as well as increased risk of subsequent cancers. Ourgene therapy program in FA is designed to enable a minimally toxic hematologiccorrection using a patient's own stem cells during the early years of life. Webelieve that the development of a broadly applicable autologous gene therapy canbe transformative for these patients.

Each of our LVV-based programs utilize third-generation, self-inactivatinglentiviral vectors to correct defects in patients' HSCs, which are the cellsfound in bone marrow that are capable of generating blood cells over a patient'slifetime. Defects in the genetic coding of HSCs can result in severe, andpotentially life-threatening anemia, which is when a patient's blood lacksenough properly functioning red blood cells to carry oxygen throughout the body.Stem cell defects can also result in severe and potentially life-threateningdecreases in white blood cells resulting in susceptibility to infections, and inplatelets responsible for blood clotting, which may result in severe andpotentially life-threatening bleeding episodes. Patients with FA have a geneticdefect that prevents the normal repair of genes and chromosomes within bloodcells in the bone marrow, which frequently results in the development of acutemyeloid leukemia ("AML"), a type of blood cancer, as well as bone marrow failureand congenital defects. The average lifespan of an FA patient is estimated to be30 to 40 years. The prevalence of FA in the US and EU is estimated to be about4,000, and given the efficacy seen in non-conditioned patients, the addressableannual market opportunity is now thought to be in the 400 to 500 range.

We currently have one LVV-based program targeting FA, RP-L102. RP-L102 is ourlead lentiviral vector based program that we in-licensed from Centro deInvestigaciones Energticas, Medioambientales y Tecnolgicas ("CIEMAT"), whichis a leading research institute in Madrid, Spain. RP-L102 is currently beingstudied in our sponsored Phase 2 registrational enabling clinical trialstreating FA patients initially at the Center for Definitive and CurativeMedicine at Stanford University School of Medicine ("Stanford") and HospitalInfantil de Nino Jesus ("HNJ") in Spain. The Phase 2 portion of the trial isexpected to enroll ten patients total from the U.S. and EU. Patients willreceive a single IV infusion of RP-L102 that utilizes fresh cells and "ProcessB" which incorporates a modified stem cell enrichment process, transductionenhancers, as well as commercial-grade vector and final drug product.

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Table of ContentsIn October 2019, at the European Society of Cell and Gene Therapy ("ESGCT") 2019Annual Congress, long-term Phase 1/2 clinical data of RP-L102, from the clinicaltrial sponsored by CIEMAT, for FA "Process A", without the use of myeloablativeconditioning was presented demonstrating evidence of increasing and durableengraftment leading to bone marrow restoration exceeding the 10% thresholdagreed to by the FDA and EMA for the ongoing registration-enabling Phase 2trial. In patient 02002, who received what we consider adequate drug product,hemoglobin levels are now similar to those in the first year after birth,suggesting hematologic correction over the long term.

During the third quarter of 2019, we received alignment from the FDA on thetrial design and the primary endpoint. This alignment was similar to thatpreviously received from the European Medicines Agency ("EMA"). Resistance tomitomycin-C, a DNA damaging agent, in bone marrow stem cells at a minimum timepoint of one year to serve as the primary endpoint for our Phase II study. InDecember 2019, we announced that the first patient of the global Phase 2 studyfor RP-L102 "Process B" for FA received investigational therapy. There will betotal of 10 patients enrolled in the global Phase 2 studies.

In December 2019, we also announced preliminary results from two pediatricpatients treated with "Process B" RP-L102 prior to development of severe bonemarrow failure in our Phase 1 trial of RP-L102 for FA. To evaluate transductionefficiency, an analysis of the proportion of the MMC-resistant colony formingcells was conducted and both patients have thus far exhibited early signs ofengraftment, including increases in blood cell lineages in one patient. Nodrug-related safety or tolerability issues have been reported.

Leukocyte Adhesion Deficiency-I (LAD-I):

LAD-I is a rare autosomal recessive disorder of white blood cell adhesion andmigration, resulting from mutations in the ITGB2 gene encoding for the Beta-2Integrin component, CD18. Deficiencies in CD18 result in an impaired ability forneutrophils (a subset of infection-fighting white blood cells) to leave bloodvessels and enter into tissues where these cells are needed to combatinfections. As is the case with many rare diseases, true estimates of incidenceare difficult; however, several hundred cases have been reported to date.

Most LAD-I patients are believed to have the severe form of the disease. SevereLAD-I is notable for recurrent, life-threatening infections and substantialinfant mortality in patients who do not receive an allogeneic HSCT. Mortalityfor severe LAD-I has been reported as 60 to 75% by age two in the absence ofallogeneic HCST.

We currently have one program targeting LAD-I, RP-L201. RP-L201 is a clinicalprogram that we in-licensed from CIEMAT. We have partnered with UCLA to leadU.S. clinical development efforts for the LAD-I program. UCLA and its Eli andEdythe Broad Center of Regenerative Medicine and Stem Cell Research is servingas the lead U.S. clinical research center for the registrational clinical trialfor LAD-I, and HNJ is serving as the lead clinical site in Spain.

The ongoing open-label, single-arm, Phase 1/2 registration enabling clinicaltrial of RP-L201 has dosed one severe LAD-I patient in the U.S. to assess thesafety and tolerability of RP-L201. The first patient was treated with RP-L201in third quarter 2019. This study has received $6.5 million CLIN2 grant awardfrom the California Institute for Regenerative Medicine ("CIRM") to support theclinical development of gene therapy for LAD-I.

In December 2019, we announced initial results from the first pediatric patienttreated with RP-L201, demonstrating early evidence of safety. Analyses ofperipheral vector copy number ("VCN"), and CD18-expressing neutrophils wereperformed through three months after infusion of RP-L201 to evaluate engraftmentand phenotypic correction. The patient exhibited early signs of engraftment withVCN myeloid levels at 1.5 at three months and CD-18 expression of 45%. No safetyor tolerability issues related to RP-L201 administration (or investigationalproduct) had been identified as of that date. The study is expected to enrollnine patients globally.

Pyruvate Kinase Deficiency (PKD):

Red blood cell PKD is a rare autosomal recessive disorder resulting frommutations in the pyruvate kinase L/R ("PKLR") gene encoding for a component ofthe red blood cell ("RBC") glycolytic pathway. PKD is characterized by chronicnon-spherocytic hemolytic anemia, a disorder in which RBCs do not assume anormal spherical shape and are broken down, leading to decreased ability tocarry oxygen to cells, with anemia severity that can range from mild(asymptomatic) to severe forms that may result in childhood mortality or arequirement for frequent, lifelong RBC transfusions. The pediatric population isthe most commonly and severely affected subgroup of patients with PKD, and PKDoften results in splenomegaly (abnormal enlargement of the spleen), jaundice andchronic iron overload which is likely the result of both chronic hemolysis andthe RBC transfusions used to treat the disease. The variability in anemiaseverity is believed to arise in part from the large number of diverse mutationsthat may affect the PKLR gene. Estimates of disease incidence have rangedbetween 3.2 and 51 cases per million in the white U.S. and EU population.Industry estimates suggest at least 2,500 cases in the U.S. and EU have alreadybeen diagnosed despite the lack of FDA-approved molecularly targeted therapies.Enrollment is currently ongoing and we anticipate treating the first patient inthe third quarter of 2020.

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Table of ContentsWe currently have one LVV-based program targeting PKD, RP-L301. RP-L301 is aclinical stage program that we in-licensed from CIEMAT. The IND for RP-L301 toinitiate a global Phase 1 study was cleared by the FDA in October 2019. Thisprogram has been granted EMA orphan drug disease designation and FDA orphan drugdisease designation ("ODD").

This global Phase 1 open-label, single-arm, clinical trial is expected to enrollsix adult and pediatric transfusion-dependent PKD patients in the U.S. andEurope. Lucile Packard Children's Hospital Stanford will serve as the lead sitein the U.S. for adult and pediatric patients, and Hospital InfantilUniversitario Nio Jess will serve as the lead site in Europe for pediatricsand Hospital Universitario Fundacin Jimnez Daz will serve as the lead site inEurope for adult patients.

Infantile Malignant Osteopetrosis (IMO):

IMO is a genetic disorder characterized by increased bone density and bone masssecondary to impaired bone resorption. Normally, small areas of bone areconstantly being broken down by special cells called osteoclasts, then madeagain by cells called osteoblasts. In IMO, the cells that break down bone(osteoclasts) do not work properly, which leads to the bones becoming thickerand not as healthy. Untreated IMO patients may suffer from a compression of thebone-marrow space, which results in bone marrow failure, anemia and increasedinfection risk due to the lack of production of white blood cells. Untreated IMOpatients may also suffer from a compression of cranial nerves, which transmitsignals between vital organs and the brain, resulting in blindness, hearing lossand other neurologic deficits.

We currently have one LVV-based program targeting IMO, RP-L401. RP-L401 is apreclinical program that we in-licensed from Lund University, Sweden. Thisprogram has been granted ODD and Rare Pediatric Disease designation from theFDA. The FDA defines a "rare pediatric disease" as a serious andlife-threatening disease that affects less than 200,000 people in the U.S. thatare aged between birth to 18 years. The Rare Pediatric Disease designationprogram allows for a sponsor who receives an approval for a product topotentially qualify for a voucher that can be redeemed to receive a priorityreview of a subsequent marketing application for a different product. We havepartnered with UCLA to lead U.S. clinical development efforts for the IMOprogram and anticipate that UCLA will serve as the lead U.S. clinical site forIMO. We intend to file an IND for IMO and commence our clinical trial in thefourth quarter of 2020.

Danon disease is a multi-organ lysosomal-associated disorder leading to earlydeath due to heart failure. Danon disease is caused by mutations in the geneencoding lysosome-associated membrane protein 2 ("LAMP-2"), a mediator ofautophagy. This mutation results in the accumulation of autophagic vacuoles,predominantly in cardiac and skeletal muscle. Male patients often require hearttransplantation and typically die in their teens or twenties from progressiveheart failure. Along with severe cardiomyopathy, other Danon disease symptomscan include skeletal muscle weakness, liver disease, and intellectualimpairment. There are no specific therapies available for the treatment of Danondisease. RP-A501 is in clinical trials as an in vivo therapy for Danon disease,which is estimated to have a prevalence of 15,000 to 30,000 patients in the U.S.and the EU, however new market research is being performed and the prevalence ofpatients may be updated in the future.

In January 2019, we announced the clearance of our IND application by the FDAfor RP-A501, and in February 2019, we were notified by the FDA that we weregranted Fast Track designation for RP-A501. University of California San DiegoHealth is the initial and lead center for our Phase 1 clinical trial.

On May 2, 2019, we presented additional preclinical data at the ASCGT annualmeeting, indicating that high VCN, in Danon disease-relevant organs in both miceand non-human primates ("NHN's"), with high concentrations in heart and livertissue (for NHP, cardiac VCN was approximately 10 times higher on average thanin skeletal muscle and central nervous system), which is consistent withreported results in several studies of heart tissue across different species.There were no treatment-related adverse events or safety issues up to thehighest dose. We have dosed three patients in the RP-A501 phase 1 clinicaltrial. We will continue further enrollment with clinical data read-outs in thefourth quarter of 2020.

As of March 2020, we have dosed three patients in the RP-A501 phase 1 clinicaltrial. This completes the first low dose cohort of the Phase 1 study. Based onthe preliminary safety and efficacy data review of this completed cohort, boththe FDA and IDMC has provided clearance to advance to a higher dose cohort inPhase 1 Trial of RP-A501 for Danon Disease. We will continue further enrollmentwith clinical data read-outs in the second half of 2020.

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In addition to its LVV and AAV programs, we also have a program evaluatingCRISPR/Cas9-based gene editing for FA. This program is currently in thediscovery phase. CRISPR/Cas9-based gene editing is a different method ofcorrecting the defective genes in a patient, where the editing is very specificand targeted to a particular gene sequence. "CRISPR/Cas9" stands for Clustered,Regularly Interspaced Short Palindromic Repeats ("CRISPR") Associated protein-9.The CRISPR/Cas9 technology can be used to make "cuts" in DNA at specific sitesof targeted genes, making it potentially more precise in delivering genetherapies than traditional vector-based delivery approaches. CRISPR/Cas9 canalso be adapted to regulate the activity of an existing gene without modifyingthe actual DNA sequence, which is referred to as gene regulation.

Strategy

We seek to bring hope and relief to patients with devastating, undertreated,rare pediatric diseases through the development and commercialization ofpotentially curative first-in-class gene therapies. To achieve these objectives,we intend to develop into a fully-integrated biotechnology company. In the near-and medium-term, we intend to develop our first-in-class product candidates,which are targeting devastating diseases with substantial unmet need, developproprietary in-house analytics and manufacturing capabilities and continue tocommence registration trials for our currently planned programs. In the mediumand long-term, we expect to submit our first biologics license applications("BLAs"), and establish our gene therapy platform and expand our pipeline totarget additional indications that we believe to be potentially compatible withour gene therapy technologies. In addition, during that time, we believe thatour currently planned programs will become eligible for priority review vouchersfrom the FDA that provide for expedited review. We have assembled a leadershipand research team with expertise in cell and gene therapy, rare disease drugdevelopment and commercialization.

We believe that our competitive advantage lies in our disease-based selectionapproach, a rigorous process with defined criteria to identify target diseases.We believe that this approach to asset development differentiates us as a genetherapy company and potentially provides us with a first-mover advantage.

Financial Overview

Since our inception, we have devoted substantially all of our resources toorganizing and staffing the Company, business planning, raising capital,acquiring or discovering product candidates and securing related intellectualproperty rights, conducting discovery, research and development activities forthe programs and planning for potential commercialization. We do not have anyproducts approved for sale and have not generated revenue from product sales.From inception through March 31, 2020, we raised net cash proceeds ofapproximately $373.1 million from investors through both equity and convertibledebt financing to fund operating activities. As of March 31, 2020, we had cash,cash equivalents and investments of $275.9 million.

Since inception, we have incurred significant operating losses. Our ability togenerate product revenue sufficient to achieve profitability will depend heavilyon the successful development and eventual commercialization of one or more ofthe current or future product candidates and programs. We had net losses of$24.7 million for the three months ended March 31, 2020 and $77.3 million forthe year ended December 31, 2019. As of March 31, 2020, we had an accumulateddeficit of $207.8 million. We expect to continue to incur significant expensesand higher operating losses for the foreseeable future as we advance our currentproduct candidates from discovery through preclinical development and clinicaltrials and seek regulatory approval of our product candidates. In addition, ifwe obtain marketing approval for any of their product candidates, we expect toincur significant commercialization expenses related to product manufacturing,marketing, sales and distribution. Furthermore, we expect to incur additionalcosts as a public company. Accordingly, we will need additional financing tosupport continuing operations and potential acquisitions of licensing or otherrights for product candidates.

Until such a time as we can generate significant revenue from product sales, ifever, we will seek to fund our operations through public or private equity ordebt financings or other sources, which may include collaborations with thirdparties and government programs or grants. Adequate additional financing may notbe available to us on acceptable terms, or at all. We can make no assurancesthat we will be able to raise the cash needed to fund our operations and, if wefail to raise capital when needed, we may have to significantly delay, scaleback or discontinue the development and commercialization of one or more productcandidates or delay pursuit of potential in-licenses or acquisitions.

Because of the numerous risks and uncertainties associated with productdevelopment, we are unable to predict the timing or amount of increased expensesor when or if we will be able to achieve or maintain profitability. Even if weare able to generate product sales, we may not become profitable. If we fail tobecome profitable or are unable to sustain profitability on a continuing basis,then we may be unable to continue our operations at planned levels and be forcedto reduce or terminate our operations.

Revenue

To date, we have not generated any revenue from any sources, including fromproduct sales, and we do not expect to generate any revenue from the sale ofproducts in the near future. If our development efforts for product candidatesare successful and result in regulatory approval or license agreements withthird parties, we may generate revenue in the future from product sales.

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Research and Development Expenses

Our research and development program ("R&D") expenses consist primarily ofexternal costs incurred for the development of our product candidates. Theseexpenses include:

expenses incurred under agreements with research institutions that conduct

research and development activities including, process development,

preclinical, and clinical activities on Rocket's behalf;

costs related to process development, production of preclinical and clinical

materials, including fees paid to contract manufacturers and manufacturing

input costs for use in internal manufacturing processes;

consultants supporting process development and regulatory activities; and

costs related to in-licensing of rights to develop and commercialize our

product candidate portfolio.

We recognize external development costs based on contractual payment schedulesaligned with program activities, invoices for work incurred, and milestoneswhich correspond with costs incurred by the third parties. Nonrefundable advancepayments for goods or services to be received in the future for use in researchand development activities are recorded as prepaid expenses.

Our direct research and development expenses are tracked on a program-by-programbasis for product candidates and consist primarily of external costs, such asresearch collaborations and third party manufacturing agreements associated withour preclinical research, process development, manufacturing, and clinicaldevelopment activities. Our direct research and development expenses by programalso include fees incurred under license agreements. Our personnel, non-programand unallocated program expenses include costs associated with activitiesperformed by our internal research and development organization and generallybenefit multiple programs. These costs are not separately allocated by productcandidate and consist primarily of:

Our research and development activities are central to our business model.Product candidates in later stages of clinical development generally have higherdevelopment costs than those in earlier stages of clinical development. As aresult, we expect that research and development expenses will increasesubstantially over the next several years as we increase personnel costs,including stock-based compensation, support ongoing clinical studies, seek toachieve proof-of-concept in one or more product candidates, advance preclinicalprograms to clinical programs, and prepare regulatory filings for productcandidates.

We cannot determine with certainty the duration and costs to complete current orfuture clinical studies of product candidates or if, when, or to what extent wewill generate revenues from the commercialization and sale of any of our productcandidates that obtain regulatory approval. We may never succeed in achievingregulatory approval for any of our product candidates. The duration, costs, andtiming of clinical studies and development of product candidates will depend ona variety of factors, including:

the scope, rate of progress, and expense of ongoing as well as any future

clinical studies and other research and development activities that we

undertake;

future clinical trial results;

uncertainties in clinical trial enrollment rates;

changing standards for regulatory approval; and

the timing and receipt of any regulatory approvals.

We expect research and development expenses to increase for the foreseeablefuture as we continue to invest in research and development activities relatedto developing product candidates, including investments in manufacturing, as ourprograms advance into later stages of development and as we conduct additionalclinical trials. The process of conducting the necessary clinical research toobtain regulatory approval is costly and time-consuming, and the successfuldevelopment of product candidates is highly uncertain. As a result, we areunable to determine the duration and completion costs of research anddevelopment projects or when and to what extent we will generate revenue fromthe commercialization and sale of any of our product candidates.

Our future research and development expenses will depend on the clinical successof our product candidates, as well as ongoing assessments of the commercialpotential of such product candidates. In addition, we cannot forecast with anydegree of certainty which product candidates may be subject to futurecollaborations, when such arrangements will be secured, if at all, and to whatdegree such arrangements would affect our development plans and capitalrequirements. We expect our research and development expenses to increase infuture periods for the foreseeable future as we seek to complete development ofour product candidates.

The successful development and commercialization of our product candidates ishighly uncertain. This is due to the numerous risks and uncertainties associatedwith product development and commercialization, including the uncertainty of:

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Table of Contents

the scope, progress, outcome and costs of our clinical trials and other

research and development activities;

the efficacy and potential advantages of our product candidates compared to

alternative treatments, including any standard of care;

the market acceptance of our product candidates;

obtaining, maintaining, defending and enforcing patent claims and other

intellectual property rights;

significant and changing government regulation; and

the timing, receipt and terms of any marketing approvals.

A change in the outcome of any of these variables with respect to thedevelopment of our product candidates that we may develop could mean asignificant change in the costs and timing associated with the development ofour product candidates. For example, if the FDA or another regulatory authoritywere to require us to conduct clinical trials or other testing beyond those thatwe currently contemplate for the completion of clinical development of any ofour product candidates that we may develop or if we experience significantdelays in enrollment in any of our clinical trials, we could be required toexpend significant additional financial resources and time on the completion ofclinical development of that product candidate.

General and Administrative Expenses

General and administrative ("G&A") expenses consist primarily of salaries andrelated benefit costs for personnel, including stock-based compensation andtravel expenses for our employees in executive, operational, finance, legal,business development, and human resource functions. In addition, othersignificant general and administrative expenses include professional fees forlegal, patents, consulting, investor and public relations, auditing and taxservices as well as other expenses for rent and maintenance of facilities,insurance and other supplies used in general and administrative activities. Weexpect general and administrative expenses to increase for the foreseeablefuture due to anticipated increases in headcount to support the continuedadvancement of our product candidates. We also anticipate that we will incurincreased accounting, audit, legal, regulatory, compliance and director andofficer insurance costs as well as investor and public relations expenses.

Interest Expense

Interest expense is related to the 2021 Convertible Notes, which mature inAugust 2021, and the 2022 Convertible Notes, which mature in August 2022.

Interest Income

Interest income is related to interest earned from investments.

Critical Accounting Policies and Significant Judgments and Estimates

Our consolidated financial statements are prepared in accordance with generallyaccepted accounting principles in the U.S. The preparation of our financialstatements and related disclosures requires us to make estimates and judgmentsthat affect the reported amounts of assets, liabilities, costs and expenses, andthe disclosure of contingent assets and liabilities in our financial statements.We base our estimates on historical experience, known trends and events andvarious other factors that we believe are reasonable under the circumstances,the results of which form the basis for making judgments about the carryingvalues of assets and liabilities that are not readily apparent from othersources. We evaluate estimates and assumptions on an ongoing basis. Actualresults may differ from these estimates under different assumptions orconditions.

Our significant accounting policies are described in more detail in our 2019Form 10-K, except as otherwise described below.

Results of Operations

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Could intentionally infecting volunteers with COVID-19 help find a cure sooner? – CBC.ca

This is an excerpt fromSecond Opinion, aweeklyroundup of eclectic and under-the-radar health and medical science news emailed to subscribers every Saturday morning.If you haven't subscribed yet, you can do that byclicking here.

As researchers around the world race under immense pressure to develop a COVID-19 vaccine, a controversial approach could potentially help get them there faster but it's incredibly risky.

The process is known as a human challenge study, and it involves intentionally infecting willing volunteers with the coronavirus that causes COVID-19 in order to test the effectiveness of potential vaccines and treatments against it.

"These are very powerful studies that could make a difference, especially since we don't know a lot about the novel coronavirus," said Seema Shah, a medical ethicist at Northwestern University and Lurie Children's Hospital of Chicago.

"They could clarify what's happening in infections with people who are not symptomatic and people who have more severe disease even if they don't have underlying conditions that put them at higher risk."

Shah said COVID-19 human challenge studies could also help identify people who have developed immunity to the coronavirus, while also helping to narrow down the growing list of potential vaccines and treatments for patients.

"If there were a couple of vaccine candidates that had gotten through safety testing and there was a question about which one of those vaccines was more likely to work, a human challenge study could be a quick way to pick the best vaccine of the candidates," she said.

"It could also be useful to study whether the vaccine itself causes different kinds of harm."

The WHOsays any potential vaccine is still at least a year away, but human challenge trials could accelerate theprocess because of the time they save in the clinical trial phase.

Typically, researchers inject thousands of study participants with a vaccine or placebo and wait for symptoms to develop an approach that can take months or years after vaccine development.

Human challenge studies instead vaccinatea small group of people and then intentionally infectthem with the virus, saving critical research time, especially during a global pandemic.

But despite the potential benefits of a controlled human challenge study on COVID-19 patients, experts say the controversial approach is an ethical minefield that could have disastrous consequences if not handled carefully.

Human challenge studies typically recruit young, healthy volunteers in an effort to keep the risk of severe medical complications low.

Thousands of potential volunteers have already pledged to participate in human challenge trials on a website called 1DaySooner, but no such studies are yet underway.

Yet given what we know and don't know about the different ways in which COVID-19 attacks the human body even in young, healthy people, how do we effectively inform participants who may be unknowingly putting themselves at severe risk?

"We know that younger people tend to tolerate COVID-19 as an illness better, but what would worry me about that is there's a lot that is still unknown," said Kerry Bowman, a bioethicist and professor of global health at the University of Toronto.

He said the potential for COVID-19 patients of all ages to face long-term health implications and even death from a virus we still know so little aboutcalls into question how truly informed participants could be on the risks of a human challenge study.

"Do you truly have an informed decision?" he said. "You have consent, but is itreally well-informed? Do people fully understand? Because if we don't understand the virus itself, I wonder about the quality of informed consent that you can ask of people."

In a new paper published in the journal Science Thursday, Shah and a team of international researchers outline an ethical framework for how human challenge studies could be effectively used to combat COVID-19.

The researchers supportdeveloping a "challenge strain" of the coronavirus a stabilizedversion of the one thatis circulating worldwide to potentially infect participants, but stopped short of advocating for the work to proceed.

"The pandemic has affected just about everyone in the world in various ways, so the potential amount of social value is unprecedented here," Shah said.

"That's why our group concluded it's really important to give challenge studies a hard look and potentially invest in laying the groundwork for doing them.

"But then make that judgment call about whether and how to do them at a later date when they're ready to go."

The World Health Organization released specific criteria this week outlining its recommended approach to conducting human challenge studies, without advocating for or against them.

Among those recommendations is a need for "strong scientific justification" for the studies, ensuring that the potential benefits outweigh risksand that the selection of participants should be done with "rigorous" informed consent.

"The overarching, really important one is to minimize risk to participants as much as possible," said bioethicist Dr. Ross Upshur, of the University of Toronto's Dalla Lana School of Public Health, who helped work on the WHO guidelines.

"You need to make sure that people understand what's being proposed:what they're going to be doing;how they're going to be managed in this situation;how their safety and their well-being is going to be protected.

"But it's also incumbent on the researchers to outline all of the uncertainties,because we may not be able to actually quantify some of those risks."

Timothy Caulfield, a Canada Research Chair in health law and policy at the University of Alberta who has researched human challenge studies, said those ethical dilemmas have historically plagued this approach.

"I understand the desire to use human challenge trials, especially in this context, because people are desperate to get a vaccine quickly, not just for clinical reasons, but also for economic and social reasons," he said.

"So the pressure is intense, but the exact reason that we have research ethics guidelines is to protect research participants."

Caulfield said the damage that could be done if a human challenge trial were to go awry would be devastating.

He points to the ethics scandal involvingJesse Gelsinger, a teenager who died in a clinical trial for gene therapy in 1999, as an example of a failed human study that set the research ethics field back immensely.

Gelsingerhad a genetic disease called ornithine transcarbamylase (OTC) that he controlled through diet and medication, but after enrolling in the trialhe was injected with an experimental therapy and died a few days later.

"Just imagine the impact that it could have on vaccine research, especially in this environment where there's so much uncertainty," Caulfieldsaid.

"If it doesn't go well and if we cut corners on research ethics standards, it could end up backfiring and being really problematic."

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Recent advancements in management and treatment of thalassemia – Express Healthcare

Dr Gaurav Kharya, Clinical Lead, Centre for Bone Marrow Transplant and Cellular Therapy, Senior Consultant, Paediatric Haematology, Oncology and Immunology, Indraprastha Apollo Hospitals, New Delhi gives detailed insights into how treatment for thalassemia at the right can save patients, importance of tests to detect the disorder and preventive measures to be taken

Thalassemia is an inherited blood disorder that causes your body to have less haemoglobin than the normal levels. It is mostly caused by mutations in the DNA of cells that make haemoglobin and carries oxygen throughout the body. The mutations associated with thalassemia are passed from parents to children. Diagnosis of thalassemia can be made by simple test either Hb electrophoresis or preferably high performance liquid chromatography (HPLC). The test should be conducted before any blood transfusion otherwise they become difficult to interpret. Subsequently, a confirmatory genetic test should be done wherever possible. Over the past few years treatments for thalassemia major have evolved:

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Gene Therapy Market Aims to Expand at Double-Digit Growth Rate|Novartis AG, Gilead Sciences Inc., UniQure NV, Spark Therapeutics LLC, Bluebird Bio,…

The worldwide for Gene Therapy marketis expected to grow at a CAGR of roughly +33% over the next five years.

Gene therapy is a test treatment that includes bringing genetic material into an individuals phones to battle or counteract ailment. Specialists are reading gene therapy for various maladies, for example, extreme joined immuno-insufficiencies, hemophilia, Parkinsons infection, disease and even HIV, through various methodologies. A gene can be conveyed to a cell utilizing a bearer known as a vector. The most widely recognized kinds of vectors utilized in gene therapy are infections. The infections utilized in gene therapy are modified to make them safe, albeit a few dangers still exist with gene therapy. The innovation is still in its infancy

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Gene Therapy Market Aims to Expand at Double-Digit Growth Rate|Novartis AG, Gilead Sciences Inc., UniQure NV, Spark Therapeutics LLC, Bluebird Bio,...

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LifeArc and MRC partnership creates new 16m fund to establish Gene Therapy Innovation Hubs – PharmiWeb.com

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BioMarin Extends Gene Therapy Leadership with DiNAQOR in a Preclinical Collaboration and License Agreement to Develop Gene Therapies for Rare Genetic…

SAN RAFAEL, Calif., May 3, 2020 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (Nasdaq: BMRN) today announced that the company has entered into a preclinical collaboration and license agreement with DiNAQOR AG (DiNAQOR), a gene therapy platform company, to develop novel gene therapies to treat rare genetic cardiomyopathies. DiNAQOR will receive an undisclosed upfront payment and is eligible to receive development, regulatory and commercial milestones on product sales in addition to tiered royalties on worldwide sales. The company did not disclose financial terms. BioMarin management reiterated its 2020 GAAP net income guidance of $20 to $80 million, inclusive of this collaboration.

The license initially covers DiNAQOR's lead program, DiNA-001 for MYBPC3 hypertrophic cardiomyopathy (HCM). Additionally, the companies will collaborate on several of DiNAQOR's other pipeline programs, and BioMarin has the option to extend the license to include these additional programs on similar terms. Reflecting the long-term commitment to the collaboration, BioMarin is simultaneously investing in DiNAQOR.

"With this agreement, BioMarin is continuing to apply its gene therapy know-how and manufacturing expertise in new areas like cardiology," said Jean-Jacques Bienaim, Chairman and Chief Executive Officer at BioMarin. "This collaboration extends our global leadership position in gene therapy and boosts our potential to transform the lives of patients worldwide with rare genetic cardiomyopathies."

"We are thrilled to collaborate with the researchers at DiNAQOR to conduct this pioneering work on the development of gene therapies for inherited cardiomyophathies," said Lon Cardon, Chief Scientific Strategy Officer and Senior Vice President at BioMarin. "We believe there is tremendous potential in combining our experience in gene therapy research and development with DiNAQOR's in-depth knowledge of genetic heart diseases."

DiNAQOR was founded and is led by several leading pharmaceutical and biotechnology executives and academics with deep cardiology and gene therapy expertise. The company's holistic approach to gene therapy is focused on gene therapies for the heart that deliver a medical solution that can safely deliver gene therapies to the heart muscle, ensure transduction of the cardiac cells, and limit the exposure of the therapy to other organs.

"BioMarin is a global leader in rare disease research, development and commercialization, and their commitment to DiNA-001 is a powerful validation of DiNAQOR's gene therapy platform," said Dr. Johannes Holzmeister, Co-Founder, Chairman and CEO at DiNAQOR. "We believe our platform has many potential applications and this milestone agreement will enable us to invest in expanding our genetic medicine pipeline."

"Momentum for gene therapies continues to build, and BioMarin has demonstrated tremendous scientific, clinical, and manufacturing leadership and expertise in the space," said Thomas Voit, M.D., Ph.D., Co-Founder and Chief Scientific Officer at DiNAQOR and Director of the Biomedical Research Centre at the Great Ormond Street Hospital and the UCL Institute of Child Health, University College London. "We are looking forward to combining our strengths to expand the promise of gene therapy treatments by targeting the heart muscle to treat rare genetic cardiomyopathies."

About HCM and MYPBC3

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic heart diseases, with about 500,000 patients diagnosed with HCM worldwide. Up to 60% of HCM cases have a genetic origin, and it is estimated that 40% of those have mutations in MYBPC3, the gene that encodes cardiac myosin-binding protein C (MyBP-C).

HCM affects the heart muscle, causing the muscle to enlarge. HCM patients have an increased risk of developing heart failure and life-threatening arrhythmias. There are no approved pharmacological treatment options available that address the underlying disease biology of HCM and invasive surgery or heart transplantation may be the only options available for patients with advanced disease.

About BioMarin

BioMarin is a global biotechnology company that develops and commercializes innovative therapies for serious and life-threatening rare genetic diseases. The Company's portfolio consists of six commercialized products and multiple clinical and pre-clinical product candidates. For additional information, please visit http://www.biomarin.com. Information on BioMarin's website is not incorporated by reference into this press release.

About DiNAQOR

Founded in 2019, DiNAQOR AG is a global gene therapy platform company focused on advancing novel solutions for patients suffering from heart disease. The company's lead preclinical program, DiNA-001 is focused on the treatment of MYBPC3-linked cardiomyopathy. DiNAQOR is headquartered in Pfffikon, Switzerland, with additional presence in London, England and Boston, Massachusetts (US). For more information visit http://www.dinaqor.com.

Forward Looking Statement

This press release contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including, without limitation, statements about: BioMarin's expectations regarding the announced collaboration, the prospects for the lead and follow on pipeline products and it's 2020 GAAP profitability. These forward-looking statements are predictions and involve risks and uncertainties such that actual results may differ materially from these statements. These risks and uncertainties include, among others: results and timing of current and planned preclinical studies and clinical trials; the content and timing of decisions by the U.S. Food and Drug Administration, the European Commission and other regulatory authorities concerning the programs; the ability to manufacture the product candidates, BioMarin's revenue for 2020, especially with the possible impact of COVID-19, and those other risks detailed from time to time under the caption "Risk Factors" and elsewhere in BioMarin's Securities and Exchange Commission (SEC) filings, including BioMarin's Quarterly Report on Form 10-Q for the quarter ended March 31, 2020, and future filings and reports by BioMarin. BioMarin undertakes no duty or obligation to update any forward-looking statements contained in this press release as a result of new information, future events or changes in its expectations.

BioMarin is a registered trademark of BioMarin Pharmaceutical Inc.

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Debra Charlesworth

BioMarin Pharmaceutical Inc.

BioMarin Pharmaceutical Inc.

(415) 455-7558

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SOURCE BioMarin Pharmaceutical Inc.

Company Codes: NASDAQ-NMS:BMRN

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BioMarin Extends Gene Therapy Leadership with DiNAQOR in a Preclinical Collaboration and License Agreement to Develop Gene Therapies for Rare Genetic...

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