Immunogen's Wild Swings Due to Lack of Information at ASCO

Many terms can be used to describe Immunogen’s (IMGN) recent stock behavior, but it seems the word “schizophrenic” is the most suitable one. Immunogen gained almost 50% in the three weeks prior to the ASCO annual meeting, just to give it all back in the eight trading sessions following the conference, thus it is clear that the rollercoaster in the company’s share price had a lot to do with what was (or was not) presented at the conference.

Immunogen is involved in multiple clinical programs, but for the past year the vast majority of the attention it has received was directed at T-DM1, which is being developed by Genentech (DNA) based on Immunogen’s technology. T-DM1 is garnering more attention than all the rest of Immoungen’s programs combined because it has all the necessary ingredients for the ultimate biotech story: Huge addressable market, a strong partner, impressive (yet preliminary) clinical activity and an opportunity to validate a disruptive technology. Accordingly, it is only reasonable to expect Immunogen to be traded in tandem with T-DM1’s development.

Wild swings in biotech stocks are commonly an outcome of clinical results publication, and indeed, the presented data at ASCO could be partially blamed for the violent market reaction. Nevertheless, in this particular case, Immunogen was affected from a lack of positive news rather than the release of negative news. Genentech had previously stated it would decide whether to advance T-DM1 into a registration trial during 2008, based on an ongoing phase II trial. This led many to believe that Genentech would use the ASCO platform to announce its intention to commence a phase III trial already this year. On the last day of the conference, when the market realized Genentech was not going to give the dramatic announcement, nor was it going to release data from the ongoing phase II trial during the conference, the reaction was brutal.

T-DM1’s Clinical Data

Genentech presented data from two phase I clinical trials with T-DM1, both showing encouraging signs of activity in advanced stage breast cancer patients. The two trials differed only in their treatment schedule, with the first trial evaluating T-DM1 given every three weeks and the second trial evaluating a weekly regimen of the same drug in the same patient population.

In my previous article, I claimed that the weekly trial has a good chance of producing better results than the every three weeks trial because certain properties of T-DM1 make it more suitable for weekly administration. The main hypothesis was that weekly administration will result in higher cumulative doses as well as continuous presence of T-DM1 in circulation. The data from the weekly phase I trial did include some encouraging signs, but it was also a little bit ambiguous.

The two trials were dose escalation studies, where cohorts of 3 patients are accrued and evaluated for side effects and clinical activity. If no severe side effects are observed, additional cohorts of three patients are recruited and treated with higher doses, until there are signs of dose limiting toxicity, and the maximum tolerated dose [MTD] is established. At the MTD, the trial is expanded to additional patients in order to validate the lack of toxicities as well as the drug’s activity. In many clinical trials, activity, in the form of tumor shrinkage or disease control is measured at the MTD, as this is the dose that would be given in future trials. If the drug is active also in lower doses, patients from these cohorts may also be included in the overall assessment.

In phase I trials, activity is typically measured by a decrease in tumor burden (tumors’ size), and patients can be stratified into 4 groups, based on their response to the drug. A complete response [CR] is defined as the disappearance of all lesions, which is very uncommon in phase I trials due to the advanced nature of the disease. A partial response [PR] is defined as a decrease of more than 30% in overall tumor burden. Stable disease [SD] is defined as anything between a decrease below 30% and an increase below 20% in tumor size. Progressive disease [PD] is defined as an increase of more than 20% in tumor burden.

Two important rates in phase I trials are objective response rate (ORR - percentage of patients who achieve CR or PR) and disease control rate (DCR - percentage of patients who achieve CR+PR+SD). Another trend investigators are always keen to see in a dose escalation trial is a dose dependent response, where higher doses lead to better clinical activity.

Before going over the data from the trials, it is important to understand that such analysis must be approached with a great deal of caution. The trials include very few patients, which may lead to inaccurate results, as normal variability has a crucial effect on the trial’s outcome. For instance, in a 15 patient trial, each patient accounts for almost 7% of total data. In addition, both trials do not include a control arm, making the comparison of the data to historical figures even more problematic.

Another issue is the fact that objective response is just an early surrogate for evaluating activity and is not necessarily correlated to other clinical end points such as overall survival and progression-free survival. Evidently, comparing results from two such trials is even more problematic, but for now, that is all we have.

The weekly trial started on the right foot, at a dose of 1.2 mg/kg per week, which is equivalent to the MTD in the every three weeks trials (3.6 mg/kg every 3 weeks). All three patients achieved a partial response, two of which were ongoing for nine months, as of Feb 29th. In the next cohort, out of three patients, only two had a PR and one patient did not respond to the drug. In addition, the two responses were maintained only for 4 months. The third cohort (2 mg/kg) had 2 PRs and one stable disease. The next dose, 2.4 mg/kg was defined as the MTD, due to the appearance of dose limiting toxicities at a higher dose, so accrual was extended at this dose level. At ASCO, Genentech reported data from 6 evaluable patients at this dose, 2 had a PR, 3 had SD and one had PD.

Based on the above data, not only did T-DM1 fail to show a dose dependent response, but there was an inverse dose-dependent response. There was, however, a clear activity at the MTD as well as at lower doses, and such fluctuations are very common in dose escalation trials. It is easy to envision a situation in which one of the patients from the lowest cohort was accrued to the MTD cohort, instead of the patient who did not respond (#12), to dramatically change the response rate at the MTD. This scenario, by itself, demonstrates the problematic nature of the data.

In addition, a comparison with the every three weeks trial raises some questions as well. In the every three weeks trial, five out of fifteen patients (33%) who were treated at the MTD achieved a PR, which is comparable to the ORR in the weekly trial. However, this comparison may be misleading. Because all doses in the weekly trial showed activity, the patients in those doses may also be included in final count. Adding these patients leads to an ORR of 60% (9 PRs out of 15). In the every three weeks trial, there was one additional patient with a PR at a lower dose than the MTD, which brings the ORR from all active doses to 37.5%, substantially lower than that of the weekly trial.

While the data from the every three weeks trial is final, there are still additional patients in the weekly trial to be reported, not to mention the fact that some of the SDs in the weekly trial could turn into PRs. The original abstract, which was submitted six months prior to the conference, included response data only from seven patients, four of which had a PR. According to the updated data presented at the conference, there appear to be six PRs among those seven patients, which implies that two additional patients advanced from SD to PR in the period between initial data disclosure to late February.

In contrast, some might claim that the response rate in the every three weeks study under-represents the real benefit of this regimen, due to the substantial number of patients with non-measurable disease. In breast cancer, non-measurable disease is typically a result of the presence of bone metastases which cannot be reliably measured by means of imaging studies. Therefore, patients with non-measurable disease cannot “achieve” an objective response but, at best, can have stable disease.

In the every three weeks trial, there were 6 patients with non-measurable disease, 4 of whom derived great benefit from T-DM1. In fact, of the 5 patients who were still benefiting from T-DM1 as of February 29th, 3 had non-measurable disease. Had it been possible to reliably assess their tumors’ size, it might have been possible to document objective responses in some of these non-measurable patients. When assessing the objective response rate only in patients with measurable disease, the weekly regimen produce comparable response rate (64%) to that observed in the every three weeks regimen (60%).

Importantly, the issue of non-measurable disease is relevant only for objective response rate, and can be dealt with by looking at progression free survival [PFS] or overall survival, which are considered more reliable surrogates for clinical benefit. Currently, PFS data is available only for the every three weeks trial, so it is impossible to compare the two regimens in that sense.

Although one might expect Genentech to determine its strategy based on final phase I data or even a larger trial for evaluating the weekly dosing of T-DM1, it appears that it has already made up its mind not to pursue the weekly regimen going forward. The decision seemed peculiar as published data from the weekly trial was still not final, however, there could be several reasons for abandoning the weekly regimen at such an early point in time.

It is possible that investigators felt they had enough clinical data at hand to conclude that there is no apparent benefit from weekly administration of T-DM1, based on response rate. Another explanation for the decision might be Genentech’s access to unpublished clinical data. Unlike phase III trials, most early stage trials are not blinded studies, so trial sponsors have constant, real-time access to the generated data. The results presented at ASCO were up to date as of February 29th, thus Genentech had three month’s worth of additional data for the reported patients as well as data for recently accrued patients.

Two obvious issues that could arise from this data set are a low response rate at the MTD or a relatively short duration of the responses. Another issue that might have emerged is increased side effects associated with continuous administration of T-DM1 on a weekly basis. An additional explanation has to do with robust data from an ongoing phase II study for the every three weeks regimen. This 100 patient trial was initiated exactly one year ago, and by now there should be plenty of response as well as PFS data available.

Looking at the bright side, it is important to remember that despite all the excitement around T-DM1, until ASCO, the only available data was from the every three weeks trial. The weekly trial is yet another demonstration of T-DM1’s clinical activity and the potential of Immunogen’s technology. Safety-wise, T-DM1 still managed to be very safe, even at up to 2-fold higher cumulative doses, which bodes well for future evaluation of this candidate in combination with additional agents.

The Road Ahead

Although Genentech did not make the highly anticipated announcement, T-DM1’s case remains intact, as Genentech still sounded enthusiastic about T-DM1 at its ASCO analyst meeting. An even more reliable indication for Genentech’s intentions could be two recently announced trials that are expected to start enrolling patients very soon.

One of these trials will evaluate T-DM1 in Herceptin resistant breast cancer patients, similarl to the ongoing phase II trial. One big difference in the new trial is the slightly different eligibility criteria which require patients to have been previously treated with Tykerb, Herceptin’s biggest competitor. Tykerb, which inhibits the same target Herceptin and T-DM1 act upon, is currently the only approved agent (in combination with Roche’s Xeloda) for Herceptin resistant patients, but so far it did not gain meaningful sales momentum. Once Genentech decides to advance T-DM1 into a registration study, this trial is expected to be amended to a larger phase III study because it may allow Genentech to use best supportive care as a control arm, rather than Tykerb+Xeloda.

The second study will evaluate T-DM1 against Herceptin+Taxotere in first line patients. In addition to being the first study to compare T-DM1 with another treatment, this trial is very unusual because it compares a targeted therapy with a highly effective chemotherapy regimen instead of adding it to the regimen. For instance, Genentech is evaluating another antibody, pertuzumab in a registration trial in the same patient population as an addition to the Herceptin+Taxotere regimen and not as a substitute. The decision to evaluate T-DM1 as a single agent, rather than doing a T-DM1+Taxotere vs. Herceptin+Taxotere trial could be perceived as a testimony of the high expectations T-DM1 raises.

In contrast, it can also be derived from fears of possible antagonism between T-DM1 and Taxotere. Although Taxotere and DM1 (the drug payload of T-DM1) both target the same cellular component (microtubules) the two drugs work in opposite directions. DM1 destabilizes microtubules and leads to their collapse, while Taxotere over-stabilizes microtubules and leads to their uncontrolled extension. It is still unclear whether combining microtubule stabilizers with destabilizers is a viable option, as published studies provide contradictory evidence, depending on dosing schedules and tumor types.

Genentech published results from experiments in mice, where the combination T-DM1+Taxotere was shown to be additive in some cases but antagonistic in others. In contrast, the addition of Taxotere to other ADCs utilizing Immunogen’s technology was found to have additive or even synergistic activity, according to data presented by the company at various scientific meetings.

There is no doubt that breast cancer represents T-DM1’s most important market and largest commercial opportunity, however, there are several potential expansions of T-DM1 beyond that market. These indications include prostate, ovarian and gastric cancers, where similarly to the case of breast cancer, only a subset of patients over-express T-DM1’s target (Her-2). There is still a heated debate about this target’s relevance outside of breast cancer, and to date, breast cancer remains the only disease for which anti Her-2 agents are approved. Nevertheless, the over-expression of Her-2 in these cancer types has been well documented and suggested to correlate with tumor aggressiveness and poor prognosis.

In prostate cancer, over-expression of Her-2 has been associated with disease progression and metastatic stage, although neither Her-2’s role in disease progression nor its prevalence among patients have been fully elucidated. Over the years, several studies found that a modest percentage of early prostate cancer patients (0-25%) but a large portion of patients with advanced disease (40-80%) overexpress Her-2. Bearing in mind that only 20-30% of breast cancer cases overexpress Her-2, and given the similar incidence of prostate cancer and breast cancer in the US, the rationale to explore T-DM1 in prostate cancer is evident.

Her-2 over-expression is estimated to occur in approximately 10-15% of ovarian cancer patients. As opposed to the complete failure of Herceptin and pertuzumab in prostate cancer, there are encouraging indications from a phase II, in which pertuzumab managed to demonstrate a very modest benefit in postponing disease progression.

It is still premature to evaluate T-DM1’s prospects and the commercial opportunity in these indications. However, T-DM1 has the potential to succeed where other Her-2 therapies have failed because it has a completely distinct mechanism of action. Antibodies like Herceptin and pertuzumab can inflict damage upon cancer cells primarily by signal disruption or by initiating an immune response against the cells. Small molecule inhibitors such as Tykerb can be effective only through signal disruption. While all three drugs have some sort of activity in various settings of breast cancer, other tumor types seem relatively resistant to their effect.

An antibody-drug conjugate [ADC] such as T-DM1 is not affected by these resistant mechanisms, as its main activity is derived of the drug payload it carries into cancer cells. In other words, as long as Her-2 is present on the outer surface of a cancer cell, T-DM1 can attack the cell, regardless of what role Her-2 plays in the biology of the disease.

In addition to the aggressive development of T-DM1, Genentech is very active with other ADC programs, although it refuses to publicly discuss its ADC preclinical pipeline. At the ASCO analyst meeting, Genentech’s representatives remained tight lipped as to when and how many ADCs they expect to get into the clinic, but that should not be interpreted as a lack of commitment to the field. According to several industry sources, Genentech currently has well over 30 ADCs in pre-clinical studies and expects to promote multiple ADCs each year into the clinic.

The best demonstration for the advanced stage of some of these agents is the recent IND filing for a new ADC, which utilizes Seattle Genetics’ (SGEN) technology. Although there is still no data with respect to this ADC’s target and composition, it was filed only two weeks after the blurry answers at the ASCO meeting.

Speaking of Seattle Genetics, the company presented very good data from a dose escalation phase I for its leading ADC, SGN-35, in Hodgkin’s Lymphoma. SGN-35 managed to achieve 5 complete responses and 7 partial responses among 38 patients, leading to an ORR of 31.5% in a clear dose dependent manner. The financial potential of SGN-35 for this indication is relatively limited, with worldwide annual market potential of $300 million to $400 million, according to the company. SGN-35 importance is in serving as a strong validation for Seattle Genetics’ technology, which will hopefully enable it to expand its ADC pipeline through partnerships and technology licensing deals.

With respect to partnered ADCs in the clinic, Seattle Genetics is lagging behind Immunogen, which has both Genentech and Sanofi-Aventis (SNY) clinically validating its ADC technology. In contrast, Seattle Genetics’ technology is currently being validated only by Curagen (CRGN), a tiny company which put all its bets on CR011-vcMMAE (the CEO promised the company would find a catchier name…).

Curagen presented quite a positive data set for CR011-vcMMAE in metastatic melanoma. Final results from a phase I trial showed a clear dose dependent response, including multiple patients with long lasting tumor shrinkage, while preliminary data from a phase II extension study included a PR and 3 SDs among 6 evaluable patients. Even more encouraging was the fact that 64% of the patients who had received the ADC at or near the MTD were still progression free after 12 weeks. Despite the preliminary nature of the PFS data, it compares favorably with past trials and is comparable with the PFS rate achieved by Synta’s (SNTA) elesclomol, the most promising agent for metastatic melanoma in the clinic.

Although the commercial potential in metastatic melanoma is relatively modest, Curagen is also evaluating CR011’s potential for treating breast cancer in a recently announced phase II trial. According to the company, CR011’s target is expressed in 25% of breast cancer patients, similarly to the prevalence of Her-2. Therefore, any signs of activity in the breast cancer study will be a transforming event for Curagen as well as Seattle Genetics, but for that investors will have to wait at least six months.

The ADC arena is becoming very active, with three important events taking place in the past several weeks alone. The first event was the Genentech’s IND filing for an ADC powered by Seattle Genetics technology, the second was the start of a phase I trial for Immunogen’s IMGN388 and the third event was the recently announced licensing agreement between Seattle Genetics and Japan based Daiichi Sankyo.

Investors should expect the remainder of the year to be even busier, both in terms of clinical data (especially for IMGN901 and T-DM1 towards year end) but mostly in terms of licensing agreements and clinical trial launches that will include the potential launch of a pivotal T-DM1 study and numerous new agents from Immunogen’s and Seattle Genetics’ partners: Genentech, Sanofi-Aventis, AstraZeneca (AZN), Biotest and Astellas (ALPMF.PK). This constantly increasing traction demonstrates how ADCs are gradually becoming a focal point in the biotech industry and more specifically, the central role Immunogen and Seattle Genetics will have as the arms merchants of the antibody industry.

Author is long IMGN, SGEN & SNTA.

Comments

[thirstycamel]

Excelent article, however proper analysis of the ADC space must include the work currently being done at MITI. The MITI data is spectacular at 60 micrograms per kilogram and the toxicity is very low.

I've owned IMGN, SGEN and currently own MEDX (a possible future player in this space). None have the promise of MITI if the data holds up.

MITI's bispecific (to T cells) data is so impressive, it is either a breakthrough or a fraud.

disclosure: long MITI

[Ohad Hammer]

No doubt MITI is one of the most exciting biotech companies out there.

www.hammerstockblog.co.../


btw, the dose was 60 micrograms per m2

[Ohad Hammer]

No doubt MITI is one of hte most exciting biotechs out there:

www.hammerstockblog.co.../

btw, the dose was 60 micrograms per m2

[investorslive]

SGEN mentioned here

www.investorslive.com/.../