Stem Cell Clinic

Rituximab Offers No Extra Benefit to Induction Chemo in ALL – Medscape

Adding the anti-CD20 monoclonal antibody rituximab (various brands) to induction chemotherapy in patients with B-precursor acute lymphoblastic leukaemia (B-ALL) does not improve outcomes, UK researchers have found in a primary analysis of phase 3 trial data.

However, a separate examination of findings from the same study may nevertheless point to an update to the genetic classification for the disease that could help in creating an overall combined clinical and genetic risk score.

The research was published as an abstract from the British Society for Haematology 60th Annual Scientific Meeting, which was cancelled due to the COVID-19 pandemic.

UKALL14 involved patients with B-ALL aged 2565 years, regardless of Philadelphia chromosome (Ph) status or CD20 expression, who were randomised to standard induction chemotherapy (SOC) with or without 4 doses of rituximab (SOC+R).

Focusing on patients recruited after an amendment to the SOC regimen in April 2012, the team conducted an intention-to-treat analysis in 288 SOC patients and 289 given SOC+R, of whom 95.5% received all 4 doses of the immunotherapy.

Adele Fielding, professor of haematology at University College London Cancer Institute, London, and colleagues report that complete remission rates, at 92.7% with SOC and 94.8% with SOC+R, were similar in the two treatment arms.

There was also no difference in minimal residual disease (MRD) rates, with 42.2% and 41.8%, respectively, negative for residual disease.

Adverse, including severe, event rates were similar between the two cohorts, and there was no difference in non-relapse mortality.

After a median follow-up of 50.5 months, the researchers calculate that the 3-year event-free survival (EFS) for patients given SOC was 41.9% versus 48.7% for those receiving SOC+R, at a hazard ratio of 0.88 (p=0.28).

This contrasts with the French GRAALL-2005/R study, in which adults aged 1859 years with CD20-positive, Phnegative ALL were randomised to chemotherapy with or without rituximab, with a total of 16 to 18 infusions given across all treatment phases.

Their results indicated that adding rituximab to the ALL chemotherapy protocol improved outcomes, increasing EFS by 33% versus chemotherapy alone (p=0.04).

Prof Fielding told Medscape News UK that, for UKALL14, they had "hypothesised that giving rituximab early would make the difference, namely in helping to eliminate MRD early on".

"We were anxious not to give too much in case of toxicity from infections. It turned out that it is not toxic and doesnt seem to work to eliminate MRD early on."

She added that, in fact, "the French data showed that too," which prompts her to wonder at the mechanism of action of rituximab in B-ALL.

"Maybe you need more doses at times when patients have functional neutrophils or macrophages, or natural killer cells."

Prof Fielding also pointed out that, in the French study, they focused on patients with Ph-negative disease and in those in whom more than 20% of blasts expressed CD20.

"An important finding from our workis that the level of CD20 expression does not correlate with response to rituximab."

Approached for comment, Rachel Kahn, research communications manager at Blood Cancer UK, said that, "the immunotherapy drug rituximab remains a vital treatment for many types of blood cancer".

She told Medscape News UK, however, that "this interesting research suggests that there may not be any additional benefit of taking this drug for people with ALL".

She highlighted that the results nevertheless suggested that patients who underwent myeloablative allogeneic stem cell transplant (MAallaSCT) appeared to derive a significant benefit from adding rituximab to SOC.

Three-year EFS was 50.7% among MAallaSCT patients given SOC alone versus 72.2% in those receiving SOC+R, at a hazard ratio of 0.47 (p=0.03), which was related to a reduction in relapse risk.

This effect was not seen in patients given reduced intensity allogeneic stem cell transplantation or in maintenance groups, prompting Rachel Kahn to call for further research to identify which patients with ALL "may benefit from taking rituximab".

Prof Fielding said that, as they "do not have any plausible biological explanation" for the finding, the team is "going to be cautious about interpreting" it.

Overall, she feels that, as rituximab is "safe, its probably better to give it to everyone", as "our ability to do that is greater than our ability to do proper flow cytometry in local centres to accurately quantify CD20".

In a separate analysis, Prof Fielding and colleagues looked at all 653 patients who started treatment both before and after the SOC regimen amendment, of whom 49% were found to have high-risk chromosomal abnormalities.

These included 31% with BCR-ABL1, 8% with KMT2A-AFF1, 9% with HoL and 5% with CK abnormalities.

CK and HoL patients had lower 3-year overall survival than the overall cohort, at 24% and 19%, respectively, versus 52%, while patients with KMT2A-AFF1 fusion had an overall survival of 44% and BCR-ABL1 patients had a similar survival to the overall group.

The team also identified a series of other chromosomal abnormalities, including 1.3% with ABL-class fusions and the same proportion with JAK-STAT abnormalities, the latter had reduced 3-year overall survival, at 35%.

In contrast, among the 3% of patients with ZNF384 fusions, only two relapsed and none died.

Having found that secondary copy number alterations affecting key genes had no impact on outcomes, the team proposed "an amendment to the genetic risk classification for adult ALL", consisting of:

very high risk: CK, HoL or JAK-STAT abnormalities

high risk: all KMT2A fusions

tyrosine kinase sensitive: BCR-ABL1 and ABL-class fusions

low-risk: ZNF384 fusions

standard risk: all other patients

The team writes: "The integration of these primary genetic risk factors with other risk factors such as age, white cell count and MRD into an overall risk score is a key goal of our current work."

Prof Fielding said that the "immediate goal" of the team is "evaluating an overall risk score in our next trial, UKALL15, which has been submitted to Cancer Research UK for funding".

Rachel Kahn commented that "this research is a key example of how important it is to continue developing risk scores based on the make-up of the cancer, which can help clinicians understand how likely someone is to respond to treatment".

"This study shows that further clues can be found based on changes to a patients chromosomes."

She continued: "The more we know about how abnormalities influence how risky a cancer is thought to be, the closer we get to being able to personalise treatment to each individual to give them the most effective treatments and the best possible chance of survival."

The study was funded by Cancer Research UK.

No conflicts of interest declared.

[However, Fielding declared to ASH : Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy.

BSH 2020: Abstracts BSH2020-OR-001 & BSH2020-OR-004

Read more:
Rituximab Offers No Extra Benefit to Induction Chemo in ALL - Medscape

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