Glycomimetics: An HSCT Vertical Play That Could Change Hematology

Written by Dan Cohen and Scott Matusow

Glycomimetics (GLYC) is a name we have covered extensively in the past, dating back to our coverage in 2017 just before their phase 1/2 data release in both front-line and relapsed/refracted (R/R) Acute Myeloid Leukemia (AML). The drug, Uproleselan (then known as GMI-1271) demonstrated both a high minimal residual disease (MRD) negativity rate and a high transplantation rate, with an improved safety profile after only a single cycle of therapy.In the final analysis of this early phase study published in the journal Blood, 56% of frontline and 69% of R/R patients achieved MRD negativity.

It should be noted that only a few of the company’s trial sites had the capacity to perform MRD analysis on these patients. Furthermore, 52% of frontline and 31% of R/R AML patients proceeded to what is considered to be potentially curative; Hematopoietic Stem Cell Transplantation (HCST).Also of note was the remarkably low severe mucositis rate of 2%, which was quite impressive for a population receiving mitoxantrone, etoposide, and cytarabine (MEC). For comparison, a phase 3 study evaluating Lintuzumab + MEC in comparison to MEC alone in a similar population demonstrated a grade 3/4 mucositis rate of 25% in the MEC arm.

It is important to remember that the so-called standard of care for the management of mucositis is cryotherapy which translated means patient are instructed to literally suck on an ‘ice-cube.’ Based on the early positive data back in 2018, we discussed pursuing an accelerated approval (AA) registration pathway using a combination of the safety (mucositis) and durability (depth and duration of response) endpoint with the company’s former management.

While this would have made for an unorthodox label, we believed it to be fitting at the time because of the unusual nature of this drug - a combination agent in oncology, which has a clear benefit in safety while improving depth of response. The Food and Drug Administration (FDA) documents clearly show that efficacy alone isn’t the only demonstrable patient benefit through which a drug can gain an AA.

Per section III.C.2 of the final FDA Guidance for Industry Expedited Programs for Serious Conditions - Drugs and Biologics:

Provides efficacy comparable to those of available therapy, while (1) avoiding serious toxicity that occurs with available therapy, (2) avoiding less serious toxicity that is common and causes discontinuation of treatment of a serious condition, or (3) reducing the potential for harmful drug interactions· Provides safety and efficacy comparable to those of available therapy but has a documented benefit, such as improved compliance, that is expected to lead to an improvement in serious outcomes."

If Uproleselan efficacy measures fail to demonstrate a significant signal separation, a pathway to approval could be carved out on the basis of safety, which would be the mucositis benefit (This also relates even stronger to a current Multiple Myeloma (MM) IST study which GLYC is a co-collaborator).

Unfortunately, the former management team steered the company into a registration pathway which to date, has been proven too long to read-out. At that time, management elected to pursue a registration pathway for full new drug application (NDA) approval and opened a phase 3 study in R/R AML. The study was negotiated with the FDA as a replacement for the two trials typically required for a NDA. Therefore, a strongly powered overall survival (OS) endpoint was agreed upon.

Additionally, former management also chose to focus their efforts on Rivipansel, which was at the time licensed out to Pfizer (NYSE: PFE) for vaso-occlusive crisis (VOC). We weren’t overly confident on the outcome of that study and didn’t want to carry the risk of locking up capital for years before the AML study would read out.

Because of this, we sold out our position in the stock back in 2018 notwithstanding, we fundamentally disagreed with that approach and vocalized our objections to the management team at that time – after 5 years and 3 delays later, the aforementioned mentioned R/R study has yet to readout.

The new management team here elected to run an interim look at approximately 80% events on the outside chance they could gain an early stoppage of the trial for efficacy. The company requested the interim look after they noted a significant slowdown in event accrual in the summer of 2022 which served as the primary motivator for this analysis.

The market viewed this as a positive and the stock ran up significantly on this long-shot speculation. But, for the sake of preserving the integrity of the original design the interim look was significantly underpowered. The current R/R study is 90% powered to show a 32% median survival benefit (HR=0.68). The interim look spent an alpha (alpha-spend) of .05, but an adequately powered interim look should have seen an alpha spend of .1 - in plain laymen’s terms, the odds were stacked against GLYC getting the trial stopped here for efficacy.

On February 15^th of this year, the company announced that the independent Data Monitoring Committee (DMC) recommended the study should continue to the originally planned final overall survival event trigger.

The DMC in its analysis also concluded that there were no safety issues, which definitely bodes well for the final read-out of this trial in which GLYC is currently guiding will occur in the 1^st half of 2024. However, this guidance may change if the trial continues to slow to a crawl concerning event triggers. If this does happen, the company may consider ending the trial themselves before the 100% event threshold is met, or ask the FDA to allow an additional endpoint (s) for registration.

On another positive note, the company disclosed recently that the pooled transplantation rate in this trial was north of 31% with a remarkably low dropout rate of just 3%. Notably, this study took place during COVID in an immune-compromised patient population, without issues in enrollment pace or dropouts. The very nature of transplantation causes a period of immune depletion with numerous studies have established increased COVID associated mortality.

The low dropout, high transplantation, and slow event accrual rates especially during the pandemic, may show an additional infectious disease benefit from Uproleselan. The overall increased compliance rate alone may qualify the trial for an AA based on the second bullet point highlighted in the FDA criteria above.

There is another study being run on Uproleselan in a different hematological setting which we believe could carve out a quicker pathway to approval and is potentially registrational: an investigator sponsored trial (IST) at Washington University in St. Louis assessing the utility of Uproleselan in a multiple myeloma (MM) conditioning regimen of high dose melphalan (HDM). This study was first posted on the NIH’s clinical trials registry under NCT04682405 in December of 2020.

Interestingly, the lead investigator for the NCI sponsored front-line study of Uproleselan, Dr. Uy, also practices medicine at the same university in St. Louis. We believe it’s possible that observations from this AML front line trial may have influenced the decision to initiate this MM study.

HDM conditioning has been the mainstay approach for decades but suffers from high toxicity rates which limit the pool of patients whom could benefit. A recent study demonstrated that Bortozemib when added to HDM failed to show meaningful benefit, sadly adding to the long standing trend of failure to improve on HDM.

In this MM patient setting, the primary endpoint in this trial seeks to improve upon diarrhea rates, which are around 72.4%, so this study should set benchmarks for safety and efficacy.

Additionally, the mucositis rate for HDM is quite high at 65.5% for any grade, 22.1% for grade 3-4, with severe infections occurring in 15.2% of patients.

The duration of stay in hospital is typically around 17-18 days before discharge due to the fragility of patients in the post-transplant setting. Incidence of bacteremia, C. Difficile infections, and time to first antibiotics are notable secondary endpoints in the study. Getting patients to discharge faster and free of GI complications should realize significant cost savings for insurance companies.

It was recently found that despite the PFS benefit here with HDM, treatments could cause a higher mutational burden upon relapse. Therefore, achieving MRD negativity should be the primary goal of therapy as it’s well established to increase patient survival (HR 0.33) - the MRD negativity rate post transplantation was 39.4% for HDM conditioning.

In this IST, the primary and secondary endpoints are focused directly on safety benefit, particularly in the GI tract. The last patient was discharged from hospital on November 11^th, which was also the time when the primary and secondary analysis wrapped up. However, a look at this trial on cancer.gov shows the study additionally has longer term efficacy exploratory endpoints.

The follow-up on these patients includes 30 day, 100 day, 6, and 12 month analysis of progression free survival (PFS) and OS endpoints, along with 100 day MRD negativity. If this trial can show MRD negativity along while hitting its primary endpoint, we would anticipate a substantial rise in the stock price upon such news. The MM market size is more than 5x that of AML, so Uproleselan could potentially be a blockbuster drug in this setting.

Given the short follow up in a setting that typically tracks PFS out to 30 months, we will be closely watching for the 100-day MRD negativity rates in addition to the diarrhea, mucositis, and infection rates. In reference to FDA criteria for an AA, we strongly believe that these endpoints set in a randomized controlled setting gives GLYC what they need for AA registration.

While GLYC has not publicly guided on potential registration of the MM trial in their latest investor deck (which still has not been updated with any expected news flow guidance as seen in prior investor decks), we reiterate again that we believe this randomized and blinded study qualifies for an AA based on the population and significant unmet need in this setting. It’s our opinion that the company will indeed file for registration here provided that the data read-out is sufficiently positive – we believe the data will be positive.

We also believe the full data set should read-out at The European Hematology Association (EHA) conference coming up June 8^th-11^th 2023. However, the company would also want to have a Breakthrough Therapy Designation in this particular MM setting first, in order to begin the high-level FDA talks such a designation affords a company seeking to potentially AA a new drug.

We do speculate that the company has already filed for Breakthrough Designation in the frontline MM setting here and should hear back from The FDA here shortly.

Let’s take a look at GLYC’s current financials:

• As of March 31, 2023, GlycoMimetics had cash and cash equivalents of $65 million as compared to $47.9 million as of December 31, 2022. During the first quarter, the company raised $28.7 million from sales of shares of common stock under its existing ATM facility.
• The company's research and development expenses were $5.4 million for the quarter ended March 31, 2023, as compared to $9.6 million for the same period in 2022.
• The company's general and administrative expenses increased to $5.5 million for the quarter ended March 31, 2023, as compared to $5.1 million for the same period in 2022.

As we can see above, GLYC is in a well-leveraged position to negotiate a potential co-development partnership due to the fact they were able to successfully use their ATM to raise their cash level to $65M from end of Q4 2022 thru Q1 2023. This allows the company to turn down partnership offers they would see as unbeneficial while also allowing themselves time while they wait for data to become available in which to negotiate an advantageous partnership deal for themselves and shareholders.

Our Outlook on GLYC and what we believe the company will achieve this year. Please note that the following below are only our opinions in which the company has not yet publicly guided on:

• We believe sometime in June/July, the company will engage with a large pharma in a co-development deal for Uproleselan in all HCST transplantation settings, with GMI-1687 as the backup target.
• We believe the MM trial being run by The Washington University School of Medicine (GLYC is named as a co-collaborator) will be successful with the primary endpoint (change/improvement in diarrhea) and will additionally show success in the exploratory endpoint of MRD negativity.
• It’s our opinion this data will presented at EHA 2023 in June (EHA abstract titles will be revealed May 11^th) with the company receiving breakthrough designation in frontline/pre-treatment MM around the same time.
• Based on the above, we think the company will seek/file an AA based on the above MM trial before the end of Q3 this year.

Also, we believe the frontline AML study being run by The National Cancer Institute In conjunction with The Alliance for Clinical Trials in Oncology, will see positive topline data (HR. 0.64 or better) which could be presented as a “late breaker” at EHA 2023 – EHA late breakers will be revealed June 1^st.

The risks involved with GLYC are as expected from a developmental stage biotech:

• Because GLYC is not a revenue producing company, it’s purely a speculation play. While we are extremely bullish on GLYC’s chances here, this is still a later developmental stage biotech. Such companies burn quite a bit of cash and can continue being cash burners for years without ever producing any profit. Global economic conditions could also drastically tighten, affecting GLYC’s ability to potentially raise additional cash. Also, the company may need to add additional endpoints of their AML R/R trial in which The FDA might not approve.
• The company also needs to establish their platform via either high-quality later-stage data (upcoming) and/or a substantial big pharma partnership. Failure to achieve these could result in a substantial decline in the company’s stock price.

However, at near $1.50 a share with the floor being absolute zero, we see GLYC as a high risk, very high reward straight vertical play. There have been numerous developmental biotech companies that have gone from this price range to triple digits over the past 10 years. While certainly plays like this are rare, they do happen:

• Jazz Pharma (JAZZ) 2008 low of around $0.75 a share to a high near $200 7 years later.
• Pharmacyclics stock price was under $1 in 2009, 6 years later acquired by AbbVie (ABBV) for $21B, roughly $250 a share.
• Anacor’s stock price was under $3 a share in 2013, ran as high as nearly $150, then acquired by Pfizer (PFE) for around $100.

The above are 3 examples of developmental biotech stocks that went on massive runs that ended and/or continue in massive success. There are many more examples of such plays, and even more examples of these small cap biotech plays that failed miserably, costing shareholders millions in losses.

We are very bullish on GLYC chances here and look forward to upcoming catalysts we mentioned above. While it’s hard to give an exact opinion on the price action here over the next year, we do believe the stock will be in double digits by then. However, we see the biggest risk here being global financial conditions and potentially the company’s R/R trial in AML not reading out in a timely manner. Notwithstanding, our research tells us the data here will be successful but as with all science, we cannot know this until we observe the final data.

Disclosure: We have a beneficial long position in the shares of GLYC

Disclaimer: This article is intended for informational and entertainment use only, and should not be construed as professional investment advice. They are our opinions only. Trading stocks is risky - always be sure to know and understand your risk tolerance. You can incur substantial financial losses in any trade or investment. Always do your own due diligence before buying and selling any stock, and/or consult with a licensed financial adviser.