Geron Corporation
Overview
Geron Corporation (GERN) is a biopharmaceutical company that currently supports the clinical stage development of a telomerase inhibitor, imetelstat, in hematologic myeloid malignancies, by Janssen Biotech, Inc., or Janssen. Early clinical data, including molecular responses in essential thrombocythemia, or ET, and remission responses, including reversal of bone marrow fibrosis, in myelofibrosis, or MF, suggest imetelstat may have disease-modifying activity by inhibiting the progenitor cells of the malignant clones for the underlying diseases.1
In November 2014, Geron entered into a collaboration and license agreement, or the Collaboration Agreement, pursuant to which the company granted Janssen the exclusive rights to develop and commercialize imetelstat worldwide for all indications in oncology, including hematologic myeloid malignancies, and all other human therapeutic uses. The Collaboration Agreement became effective in December 2014 and the company received $35 million from Janssen as an upfront payment. Additional consideration under the Collaboration Agreement includes potential payments of up to an aggregate maximum total of $900 million for the achievement of development, regulatory and sales milestones, as well as royalties on worldwide net sales of imetelstat. Janssen may terminate the Collaboration Agreement at any time for convenience or due to a safety-related concern. Under the Collaboration Agreement, Janssen is wholly responsible for development, manufacturing, seeking regulatory approval for, and commercialization of imetelstat worldwide. All worldwide regulatory, development, manufacturing and promotional activities related to imetelstat are being managed through a joint governance structure. The joint governance structure includes a Joint Steering Committee, or JSC, with equal membership from both companies.
Janssen is currently conducting two clinical trials of imetelstat: IMbark, a Phase 2 trial in MF, in which the first patient was dosed in September 2015; and IMerge, a Phase 2/3 trial in myelodysplastic syndromes, or MDS, in which the first patient was dosed in January 2016. The company is contributing 50% of the development costs for these studies, which Janssen is solely conducting.
IMerge is a two-part clinical trial evaluating imetelstat in transfusion dependent patients with Low or Intermediate-1 risk MDS who have relapsed after or are refractory to prior treatment with an erythropoiesis stimulating agent, or ESA. Part 1 of the trial is designed as a Phase 2, open-label, single-arm trial to assess the efficacy and safety of imetelstat. Efficacy assessments include hematologic improvement and reduction in transfusion requirements. Part 2 of the trial is planned as a Phase 3 double-blind, randomized, controlled trial in approximately 170 patients. The primary efficacy endpoint is the rate of red blood cell transfusion independence, or RBC-TI, lasting at least 8 weeks. Key secondary endpoints include the rates of red blood cell transfusion independence lasting at least 24 weeks and hematologic improvement.
In September 2016, an internal data review of IMerge was conducted, and the JSC determined to continue IMerge unmodified. In April 2017, a second internal review of IMerge was completed, and the JSC determined to continue IMerge unmodified.
In Part 1 of IMerge, 32 patients were enrolled, of which a subset of 13 patients had not received prior treatment with either a hypomethylating agent, or HMA, or lenalidomide and did not have a del(5q) chromosomal abnormality. As of May 2017, this 13-patient subset showed an increased durability and rate of transfusion independence compared to the overall trial population (>8-week RBC-TI: 53.8% vs 34.4%). The safety profile in Part 1 was consistent with prior clinical trials of imetelstat in hematologic malignancies, and no new safety signals were identified. The most common adverse events were cytopenias, which were manageable, and included Grade 3/4 neutropenia and thrombocytopenia.
Based on these data from the 13-patient subset, the JSC decided to amend Part 1 of the protocol to enroll approximately 20 additional patients who are non-del(5q) and naïve to HMA and lenalidomide treatment in order to increase the experience and confirm the benefit-risk profile of imetelstat dosed at 7.5 mg/kg every four weeks in this refined target patient population to inform a decision to treat patients in this population in Part 2 of IMerge. Such protocol amendment is expected to be submitted by Janssen to regulatory authorities for review and clearance, and must also be reviewed and approved by each clinical sites institutional review board/ethics committee prior to being implemented. The company expect enrollment into the expanded Part 1 to begin in the fourth quarter of 2017.
Detailed results for Part 1 of IMerge, including key secondary endpoints of hematologic improvement and rate of RBC-TI lasting at least 24 weeks, as well as duration of response and detailed safety information will be submitted for presentation at a major medical conference.
Separately, a data package and proposed refinements to the trial design for Part 2 of IMerge were previously provided to the United States Food and Drug Administration, or FDA, by Janssen following the internal data review completed by Janssen in April 2017, and related interactions between Janssen and the FDA are ongoing.
Janssen has not committed to begin Part 2 of IMerge. The company believe development of imetelstat in Part 2 of IMerge by Janssen will be dependent on the results of the protocol-specified primary analysis for IMbark and/or an affirmative Continuation Decision. In addition, The company expect feedback from FDA interactions, data from the expanded Part 1, continuing data from IMbark, including the internal data review in the first quarter of 2018, and the totality of imetelstat program information will inform Janssens decision whether to move forward to Part 2 of IMerge. Further delays in decision-making related to whether to commence Part 2 of IMerge, including a decision by Janssen to delay such decision-making pending the completion of the protocol-specified primary analysis for IMbark, would further impede the advancement of imetelstat development in lower risk MDS.
IMbark was originally designed as a Phase 2 clinical trial to evaluate two dose levels of imetelstat (either 4.7 mg/kg or 9.4 mg/kg administered every three weeks) in approximately 200 patients with Intermediate-2 or High risk MF who have relapsed after or are refractory to prior treatment with a janus kinase, or JAK, inhibitor. The co-primary efficacy endpoints for the trial are spleen response rate, defined as the proportion of patients who achieve a >35% reduction in spleen volume assessed by imaging, and symptom response rate, defined as the proportion of patients who achieve a >50% reduction in Total Symptom Score, at 24 weeks.
In September 2016, a planned internal review of data from IMbark was completed. From this first internal data review, the JSC determined that activity in the 4.7 mg/kg dosing arm did not warrant further investigation of that dose, and accordingly the 4.7 mg/kg dosing arm was closed to new patient enrollment. The JSC also determined that the 9.4 mg/kg dosing arm in IMbark warranted further investigation because encouraging trends in the efficacy data were observed, but new patient enrollment to this arm was suspended because an insufficient number of patients met the protocol defined interim efficacy criteria at 12 weeks. Following this first internal data review, the JSC determined to continue the trial to obtain additional and more mature data, and patients remaining in the treatment phase of IMbark were permitted to receive imetelstat.
In April 2017, a second internal review of IMbark was completed, which included data from the approximately 100 patients who were enrolled in the trial, with each dosing arm analyzed separately. Based on this second internal data review, the JSC determined the following:
- The safety profile was consistent with prior clinical trials of imetelstat in hematologic malignancies, and no new safety signals were identified.
- The data support 9.4 mg/kg as an appropriate starting dose for the relapsed or refractory MF patient population.
- In these relapsed or refractory MF patients treated in the 9.4 mg/kg dosing arm, the spleen volume response rate observed to date was less than that reported in front-line MF patients treated in trials with other drugs. However, activity within multiple outcome measures was observed with imetelstat treatment, which suggests potential clinical benefit in this relapsed or refractory MF patient population. These outcome measures included a range of spleen volume reductions, reductions in Total Symptoms Score, and improvements in hematologic parameters, such as anemia and peripheral blood counts. In addition, the data suggest there may be a potential survival benefit associated with imetelstat treatment in these patients.
The trial continues without any modifications, and patients remaining in the treatment phase may continue to receive imetelstat. Enrollment of new patients to the trial remains suspended because the total number of patients enrolled to date is adequate to perform the protocol-specified primary analysis. All safety and efficacy assessments will be conducted as planned in the protocol, which includes an assessment of a potential survival benefit associated with imetelstat treatment. To date, median overall survival has not yet been reached in either dosing arm. The company also expect Janssen to perform an internal data review in the first quarter of 2018 to enable a potential protocol amendment to allow the long-term treatment and follow-up of patients, including for survival, beyond the current April 2018 per-protocol end-of-study date.
In July 2017, the JSC agreed that the timing of the protocol-specified primary analysis for IMbark will begin upon the earlier of either a pre-specified number of deaths occurring in the trial or the end of the third quarter of 2018. Following completion of this primary analysis, which would include an assessment of potential survival benefit associated with imetelstat treatment, The company expect Janssen to notify the company of its Continuation Decision. The primary analysis may not occur at all if IMbark is terminated early based on preliminary or ongoing data assessments, safety concerns or for any other reason, or placed on clinical hold or suspended by a regulatory authority for an extended period of time, under which circumstances Janssen must instead notify the company of its Continuation Decision by the date that is approximately 24 months after the initiation of IMerge.
Geron expect continuing data from IMbark, including the internal data review in the first quarter of 2018, the protocol-specified primary analysis for IMbark, potential regulatory feedback, the totality of imetelstat program information, including an assessment of the evolving treatment landscape in MF and the potential application of imetelstat in multiple hematologic malignancies, including MDS, will inform Janssens decision whether to continue development of imetelstat. The company expect that without an adequate survival benefit in relapsed or refractory MF, Janssen would decide to discontinue the imetelstat program and terminate the Collaboration Agreement. Further delay in the timing of the Continuation Decision, or a negative Continuation Decision, which would result in termination of the Collaboration Agreement by Janssen, could increase its development costs and impair its ability to earn revenues from milestone payments or royalties under the Collaboration Agreement, any of which would severely and adversely affect its business and business prospects and the future of imetelstat.
Financial Overview
Geron had approximately $117.2 million in cash and investments as of June 30, 2017. To grow and diversify its business, The company plan to continue its business development efforts to identify, and seek to acquire and/or in-license other oncology products, product candidates, programs or companies. Acquisition or in-licensing opportunities that The company may pursue could materially affect its liquidity and capital resources and may require it to incur indebtedness or seek equity capital, or both. While the company reported a small profit for the year ended December 31, 2015 due to its recognition of revenue in connection with the upfront payment from Janssen under the Collaboration Agreement, until 2015 it had never been profitable. The companyhave incurred significant net losses since its inception in 1990, resulting principally from costs incurred in connection with its research and development activities and from general and administrative costs associated with its operations. As of June 30, 2017, The company had an accumulated deficit of $971.5 million. Since its inception, The company primarily have financed its operations through the sale of equity securities, interest income on its marketable securities and payments it received under its collaborative and licensing arrangements.
Substantially all of its revenues to date have been payments under collaborative agreements, and milestones, royalties and other revenues from its licensing arrangements. The company currently have no source of product revenue. The significance of future losses, future revenues and any potential future profitability will depend primarily on whether Janssen continues to develop and advance imetelstat and the clinical and commercial success of imetelstat, which would result in potential future revenues to it in the form of milestone payments and royalties under the Collaboration Agreement, and whether the company in-license or acquire other oncology products, product candidates, programs or companies in order to grow and diversify its business. There can be no assurance that it will receive any milestone payments or royalties from Janssen in the future, or at all. In addition, if Janssen does not perform in the manner it expect or fulfill its responsibilities in a timely manner, or at all, including with respect to enrolling additional patients in Part 1 of IMerge and/or obtaining longer-term efficacy and safety data from IMbark to enable an assessment of potential survival benefit associated with imetelstat treatment, the clinical development, manufacturing, regulatory approval and/or commercialization of imetelstat could be delayed or terminated, and it could become necessary for it to assume responsibility for the clinical development, manufacturing, regulatory approval and/or commercialization of imetelstat at its own expense. In any event, imetelstat will require significant additional clinical testing prior to possible regulatory approval in the United States and other countries, and it do not expect imetelstat to be commercially available for many years, if at all.
