Geron Company (NASDAQ:GERN) is creating imetelstat for decrease threat myelodysplastic syndromes (LR-MDS) and myelofibrosis (MF). Whilst GERN introduced good fortune in its section 3 IMerge find out about in LR-MDS in January 2023, the MF indication is not as with regards to approval with an intervening time research now not anticipated from a significant section 3 find out about till 2024. As such, this text takes a take a look at GERN’s odds of approval in LR-MDS and the contest, present and attainable, in that indication.
Imetelstat: Able for regulatory submission in LR-MDS
GERN’s IMerge find out about recruited sufferers with LR-MDS who have been both refractory to, or ineligible for, erythropoiesis stimulating brokers (ESA). If you’ll’t take a drug to stimulate erythropoiesis you may well be desiring a large number of blood transfusions. GERN’s imetelstat, a telomerase inhibitor, has the skill to scale back the will for blood transfusions in LR-MDS.
On January 4, 2023, GERN introduced that its IMerge find out about met the main endpoint with 39.8% of imetelstat handled sufferers reaching transfusion independence of 8 8 weeks or extra, in comparison to simply 15% of sufferers within the placebo staff (P < 0.001). Splitting the knowledge into sufferers with one of those mobile of their blood known as ringed sideroblasts (RS+), and the ones with out ringed sideroblasts (RS-), we see that imetelstat outperformed placebo in each teams. Differently of splitting the knowledge is to take a look at sufferers with very prime transfusion burden, who require greater than six transfusions each 8 weeks, in comparison to the ones with prime transfusion burden, once more we see that imetelstat outperformed placebo.
At the protection facet, whilst there have been discounts in more than a few mobile counts, reminiscent of low neutrophil depend (neutropenia), they have been manageable and so the velocity of significant infections wasn’t considerably larger by way of imetelstat. In a similar fashion, whilst there have been will increase in serum ranges of sure liver enzymes, there have been no Hy’s legislation circumstances, this means that we’d are expecting imetelstat to move directly to reason drug-induced liver harm.
GERN sees a complete addressable marketplace of ~ $3.5B in LR-MDS, the place the IMerge find out about has already proven a transparent advantage of imetelstat, and ~ $3.5B in myelofibrosis, for which imetelstat has the IMpactMF find out about. On the subject of the IMpactMF find out about, we would possibly not see the rest till a 2024 intervening time research. However, effects from a section 1 aggregate find out about of imetelstat with ruxolitinib in MF (IMproveMF) may just come by way of year-end 2023, so the MF indication remains to be price bearing in mind even within the near-term.
An present competitor: Reblozyl
At this level it’s price bringing up a significant competitor in LR-MDS, Bristol-Myers Squibb’s (BMY) Reblozyl (luspatercept), which is already licensed in sufferers with RS+ very low- to intermediate-risk MDS who require no less than two devices of pink blood cells each 8 weeks.
The approval of Reblozyl within the MDS indication was once supported by way of the double-blind, placebo-controlled, section 3 Medalist find out about in very low- to intermediate-risk MDS sufferers. Within the Medalist find out about, 38% of sufferers handled with luspatercept completed transfusion independence of no less than 8 weeks all over weeks 1-24 of the find out about. Via comparability, simply 13% of the placebo staff completed the 8 week transfusion independence endpoint.
Evaluating the result of GERN’s IMerge find out about to the Medalist find out about of Reblozyl, Assessment Vantage’s Jacob Plieth notes that whilst Medalist did not supply knowledge from RS- MDS sufferers, it nonetheless sees off-label use in RS- sufferers, and so the true differentiator for imetelstat may well be the knowledge in sufferers with prime transfusion burden. In Medalist, within the subgroup of sufferers requiring no less than six devices of pink blood cells in keeping with 8 weeks at baseline, simply 9% (6/66) of sufferers handled with imetelstat completed transfusion independence for 8 weeks or longer. This was once nonetheless greater than the subset of placebo staff sufferers with very prime transfusion burden, the place simply 1% (1/33) completed transfusion independence of no less than 8 weeks. Recall that during Determine 2 above, imetelstat produced a 33.9% fee of 8 weeks or extra transfusion independence, in sufferers requiring greater than six devices of pink blood cells in keeping with 8 weeks at baseline.
Whilst Medalist checked out sufferers who had failed an ESA, have been not going to answer an ESA or had discontinued an ESA because of an hostile tournament, there may be knowledge for Reblozyl out of doors of that affected person staff.
Reblozyl in ESA-naive sufferers
On October 31, 2022, BMY introduced certain topline effects from a section 3 find out about of Reblozyl vs epoetin alfa (an ESA) in ESA-naive sufferers with very low/low/intermediate-risk MDS. Exact percentages on transfusion independence were not offered on the time of the clicking unlock, however we will be informed a bit extra about this trial from probably the most fresh summary discussing it, to be had on Might 25, 2023, as a part of the 2023 annual assembly on the American Society of Medical Oncology (ASCO).
The ASCO summary notes that 58.5% of sufferers handled with luspatercept completed the main endpoint of pink blood mobile transfusion independence (RBC-TI) of â¥ 12 weeks, with a concurrent imply hemoglobin build up of â¥ 1.5 g/dL throughout the first 24 weeks. Via comparability 31.2% of sufferers handled with epoetin alfa completed the main endpoint. Put merely, luspatercept carried out just about two times in addition to an ESA in to start with ESA-naive sufferers (necessarily a first-line surroundings).
As such, whilst the former LR-MDS remedy paradigm may were more practical (Determine 5), with sufferers failing first-line ESA’s progressing to Reblozyl or imetelstat (if licensed), the remedy paradigm can have modified relatively nowadays 2022.
Nonetheless, even supposing sufferers had to take a look at Reblozyl first, imetelstat can nonetheless see use, and GERN is conscious about this chance. As an example, GERN’s Might Company Presentation features a slide noting that in accordance with a marketplace analysis with 50 US working towards hematologists, there may be an anticipated 55% usage of imetelstat in “Reblozyl-experienced frontline sufferers,” (Determine 6, center column).
Odds of FDA acclaim for Imetelstat in LR-MDS
I believe it’s most likely the FDA will approve GERN’s imetelstat in LR-MDS, particularly in accordance with the energy of the efficacy knowledge in closely transfusion-dependent sufferers. Additional, whilst Reblozyl may see off-label use in RS- MDS sufferers, GERN’s IMerge find out about supplies double-blind, placebo-controlled knowledge in RS- sufferers who’re refractory or ineligible for ESA’s.
On the subject of the security of the drug, I don’t believe there may be the rest so relating to as to forestall approval. I believe the security will also be regarded as by way of the prescriber within the context of that efficacy and the severity of a given affected person’s situation. Although we shouldn’t have a lot knowledge from luspatercept refractory sufferers, doctor revel in on this situation can develop over the years and naturally GERN may just conform to run research in that inhabitants as a part of a post-approval requirement.
I in point of fact do not see the questions of safety or the truth that the remedy panorama has modified with luspatercept as being more likely to lead to imetelstat being rejected by way of the FDA. As an alternative I would believe that there’s all the time a possibility of an New Drug Software (NDA) now not being licensed on account of a chemistry production and controls (CMC) problems. GERN hasn’t ever were given a drug licensed and so whilst they are going to have an skilled staff, the outfit itself hasn’t confirmed itself in that regard.
GERN is ready to publish its NDA in June with a pre-NDA assembly already finished and resulting in no alternate in submission plans, that bodes neatly for the chances of approval. GERN has asked a concern overview, which might see a overview time of six months, following an preliminary two month length for the FDA to dossier or refuse-to-file the NDA. An 8 month overview length general then would permit approval in Q1’24 and the H1’24 imetelstat release GERN is getting ready for.
GERN reported Q1’23 profits on Might 11, 2023. The corporate had $409.2M in money and marketable securities as of March 31, 2023. R&D bills have been $27.2M in Q1’23 and G&A was once $12.9M. Web loss for Q1’23 was once $38.1M and internet money utilized in running actions was once $46.4M. GERN predicts its present sources will fund operations till the tip of Q3’25 and we are relatively depending on that prediction as the present fee of money burn would not be a excellent estimate of money burn going ahead as the corporate strikes from the past due scientific level to the economic level. It will have to be famous that GERN has $51.4M in noncurrent debt from its mortgage settlement arrange in 2020 with Hercules and Silicon Valley Financial institution.
After all, GERN’s money and marketable securities stability, internet of its debt, of $350M+ method GERN does not wish to discover a spouse to release imetelstat in LR-MDS.
As of Might 5, there have been 508,766,846 stocks of GERN’s not unusual inventory exceptional, similar to a marketplace cap of $1.67B (at $3.28 in keeping with proportion).
GERN is executing within the health center with good fortune in IMerge, and different research set to readout in past due 2023 (section 1), 2024 (IMpactMF intervening time) and past. I believe the drug is more likely to get a concern overview given the choices to be had to sufferers failing an ESA or Reblozyl are restricted and the drug gives a compelling get advantages in LR-MDS sufferers with prime transfusion dependence. At the business facet GERN is easily ready having were given a money lift out of the best way in Q1’23 that means additional dilution is not going within the near-term.
I view GERN as a purchase in accordance with quite a lot of catalysts forward of which I be expecting maximum to damage within the corporate’s choose. The primary will be the acceptance of the imetelstat NDA for substantive overview (most likely in August, two months after June submission) relatively than a refusal-to-file letter. The second one can be the possibility of the FDA to grant a concern overview, relatively than a typical overview, and the 3rd can be the opportunity of certain effects from a section 1 aggregate find out about of imetelstat and ruxolitinib in MF in past due 2023.
The hazards of any lengthy in GERN are a number of fold, a couple of of which can be price discussing right here. Originally, any delays in filing the imetelstat NDA in June may just reason the inventory to fall. Secondly, a CMC factor is all the time an opportunity resulting in refusal-to-file letter, which might reason GERN inventory to fall, as would a refusal-to-file letter for another explanation why. Finally, GERN’s imetelstat NDA may not be granted a concern overview, which might additionally reason the inventory to fall.
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